ID PDE5A_HUMAN Reviewed; 875 AA. AC O76074; A0AV69; A8K2C4; O75026; O75887; Q86UI0; Q86V66; Q9Y6Z6; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2011, sequence version 2. DT 27-MAR-2024, entry version 212. DE RecName: Full=cGMP-specific 3',5'-cyclic phosphodiesterase {ECO:0000305}; DE EC=3.1.4.35 {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:9714779}; DE AltName: Full=cGMP-binding cGMP-specific phosphodiesterase; DE Short=CGB-PDE; GN Name=PDE5A {ECO:0000312|HGNC:HGNC:8784}; Synonyms=PDE5; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PDE5A1 AND PDE5A2), FUNCTION, RP CATALYTIC ACTIVITY, AND VARIANT VAL-93. RX PubMed=9714779; DOI=10.1016/s0378-1119(98)00303-5; RA Loughney K., Hill T.R., Florio V.A., Uher L., Rosman G.J., Wolda S.L., RA Jones B.A., Howard M.L., McAllister-Lucas L.M., Sonnenburg W.K., RA Francis S.H., Corbin J.D., Beavo J.A., Ferguson K.; RT "Isolation and characterization of cDNAs encoding PDE5A, a human cGMP- RT binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase."; RL Gene 216:139-147(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM PDE5A1), AND VARIANT RP VAL-93. RC TISSUE=Lung, and Placenta; RX PubMed=9716380; DOI=10.1046/j.1432-1327.1998.2550391.x; RA Yanaka N., Kotera J., Ohtsuka A., Akatsuka H., Imai Y., Michibata H., RA Fujishige K., Kawai E., Takebayashi S., Okumura K., Omori K.; RT "Expression, structure and chromosomal localization of the human cGMP- RT binding cGMP-specific phosphodiesterase PDE5A gene."; RL Eur. J. Biochem. 255:391-399(1998). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A1), AND VARIANT VAL-93. RC TISSUE=Prostate, and Skeletal muscle; RX PubMed=9642111; DOI=10.1006/bbrc.1998.8769; RA Stacey P., Rulten S., Dapling A., Phillips S.C.; RT "Molecular cloning and expression of human cGMP-binding cGMP-specific RT phosphodiesterase."; RL Biochem. Biophys. Res. Commun. 247:249-254(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2), AND VARIANT VAL-93. RC TISSUE=Lung; RA Kotera J., Imai Y., Omori K.; RT "Molecular cloning and characterization of human cGMP-specific RT phosphodiesterase 5A2 cDNA."; RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2). RC TISSUE=Colon carcinoma; RA Sopory S., Visweswariah S.S.; RT "PDE5A splice variants in T84 cells."; RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1), AND VARIANT RP VAL-93. RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 157-411. RC TISSUE=Trabecular meshwork; RX PubMed=10393044; RA Zhou L., Thompson W.J., Potter D.E.; RT "Multiple cyclic nucleotide phosphodiesterases in human trabecular meshwork RT cells."; RL Invest. Ophthalmol. Vis. Sci. 40:1745-1752(1999). RN [10] RP PHOSPHORYLATION BY PRKG1. RX PubMed=11723116; DOI=10.1074/jbc.m106562200; RA Rybalkin S.D., Rybalkina I.G., Feil R., Hofmann F., Beavo J.A.; RT "Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in RT smooth muscle cells."; RL J. Biol. Chem. 277:3310-3317(2002). RN [11] RP FUNCTION. RX PubMed=25799991; DOI=10.1038/nature14332; RA Lee D.I., Zhu G., Sasaki T., Cho G.S., Hamdani N., Holewinski R., Jo S.H., RA Danner T., Zhang M., Rainer P.P., Bedja D., Kirk J.A., Ranek M.J., RA Dostmann W.R., Kwon C., Margulies K.B., Van Eyk J.E., Paulus W.J., RA Takimoto E., Kass D.A.; RT "Phosphodiesterase 9A controls nitric-oxide-independent cGMP and RT hypertrophic heart disease."; RL Nature 519:472-476(2015). RN [12] {ECO:0007744|PDB:1T9R, ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF} RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 534-858 IN COMPLEX WITH ZINC, RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ALA-767; GLN-775 AND TRP-853, RP AND COFACTOR. RX PubMed=15260978; DOI=10.1016/j.molcel.2004.07.005; RA Zhang K.Y.J., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S., RA Hsieh D., Neiman J., West B.L., Zhang C., Milburn M.V., Kim S.-H., RA Schlessinger J., Bollag G.; RT "A glutamine switch mechanism for nucleotide selectivity by RT phosphodiesterases."; RL Mol. Cell 15:279-286(2004). RN [13] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 537-860 IN COMPLEX WITH ZINC; RP MAGNESIUM AND THE INHIBITORS SILDENAFIL; TADALAFIL AND VARDENAFIL, RP COFACTOR, AND ACTIVITY REGULATION. RX PubMed=12955149; DOI=10.1038/nature01914; RA Sung B.-J., Hwang K.Y., Jeon Y.H., Lee J.I., Heo Y.-S., Kim J.H., Moon J., RA Yoon J.M., Hyun Y.-L., Kim E., Eum S.J., Park S.-Y., Lee J.-O., Lee T.G., RA Ro S., Cho J.M.; RT "Structure of the catalytic domain of human phosphodiesterase 5 with bound RT drug molecules."; RL Nature 425:98-102(2003). CC -!- FUNCTION: Plays a role in signal transduction by regulating the CC intracellular concentration of cyclic nucleotides. This CC phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP CC (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide- CC generated cGMP (PubMed:15489334). {ECO:0000269|PubMed:15489334, CC ECO:0000269|PubMed:9714779}. CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746, CC ChEBI:CHEBI:58115; EC=3.1.4.35; CC Evidence={ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:9714779}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958; CC Evidence={ECO:0000305|PubMed:15260978}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:12955149, ECO:0000269|PubMed:15260978}; CC Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per CC subunit: site 1 preferentially binds zinc, while site 2 has a CC preference for magnesium. Tightly binds zinc. CC {ECO:0000269|PubMed:12955149, ECO:0000269|PubMed:15260978}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:12955149}; CC Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations CC per subunit: site 1 preferentially binds zinc, while site 2 has a CC preference for magnesium. Binds magnesium less tightly than zinc. CC {ECO:0000269|PubMed:12955149}; CC -!- ACTIVITY REGULATION: Sildenafil (Viagra) is a highly selective and CC potent inhibitor of PDE5A and is effective in the treatment of penile CC erectile dysfunction. Also inhibited by zaprinast. CC {ECO:0000269|PubMed:12955149}. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from CC 3',5'-cyclic GMP: step 1/1. CC -!- INTERACTION: CC O76074; Q13976: PRKG1; NbExp=4; IntAct=EBI-9023531, EBI-3952014; CC O76074; Q9NZD8: SPG21; NbExp=3; IntAct=EBI-9023531, EBI-742688; CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=PDE5A1; CC IsoId=O76074-1; Sequence=Displayed; CC Name=PDE5A2; CC IsoId=O76074-2; Sequence=VSP_004591; CC -!- TISSUE SPECIFICITY: Expressed in aortic smooth muscle cells, heart, CC placenta, skeletal muscle and pancreas and, to a much lesser extent, in CC brain, liver and lung. CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two CC putative divalent metal sites and an N-terminal regulatory domain which CC contains two homologous allosteric cGMP-binding regions, A and B. CC -!- PTM: Phosphorylation is regulated by binding of cGMP to the two CC allosteric sites (By similarity). Phosphorylation by PRKG1 leads to its CC activation. {ECO:0000250, ECO:0000269|PubMed:11723116}. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC {ECO:0000305}. CC -!- CAUTION: Was initially thought to act as a major regulator of cardiac CC hypertrophy in myocytes and muscle and investigations have been made on CC selective PDE5A inhibitors that could protect against cardiovascular CC disease. However, while PDE5A regulates nitric-oxide-generated cGMP, CC nitric oxide signaling is often depressed by heart disease, limiting CC its effect. Moreover, clinical trial using PDE5A inhibitors were CC disappointing. {ECO:0000269|PubMed:25799991}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF043731; AAC63967.1; -; mRNA. DR EMBL; AF043732; AAC63968.1; -; mRNA. DR EMBL; AB001635; BAA33372.2; -; Genomic_DNA. DR EMBL; D89094; BAA28945.1; -; mRNA. DR EMBL; AJ004865; CAA06170.1; -; mRNA. DR EMBL; AB015656; BAA81667.1; -; mRNA. DR EMBL; AY264918; AAP21809.1; -; mRNA. DR EMBL; AK290189; BAF82878.1; -; mRNA. DR EMBL; AC093752; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC080089; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC126233; AAI26234.1; -; mRNA. DR EMBL; AY266363; AAP31235.1; -; mRNA. DR CCDS; CCDS34055.1; -. [O76074-2] DR CCDS; CCDS3713.1; -. [O76074-1] DR PIR; JW0106; JW0106. DR RefSeq; NP_001074.2; NM_001083.3. [O76074-1] DR RefSeq; NP_236914.2; NM_033430.2. [O76074-2] DR RefSeq; NP_246273.2; NM_033437.3. DR PDB; 1RKP; X-ray; 2.05 A; A=535-860. DR PDB; 1T9R; X-ray; 2.10 A; A=531-875. DR PDB; 1T9S; X-ray; 2.00 A; A/B=534-858. DR PDB; 1TBF; X-ray; 1.30 A; A=534-858. DR PDB; 1UDT; X-ray; 2.30 A; A=537-860. DR PDB; 1UDU; X-ray; 2.83 A; A/B=537-860. DR PDB; 1UHO; X-ray; 2.50 A; A=537-860. DR PDB; 1XOZ; X-ray; 1.37 A; A=534-875. DR PDB; 1XP0; X-ray; 1.79 A; A=534-875. DR PDB; 2CHM; X-ray; 1.60 A; A=534-656, A=682-858. DR PDB; 2H40; X-ray; 1.85 A; A=535-860. DR PDB; 2H42; X-ray; 2.30 A; A/B/C=535-860. DR PDB; 2H44; X-ray; 1.80 A; A=535-860. DR PDB; 2XSS; X-ray; 2.50 A; A/B=346-509. DR PDB; 3B2R; X-ray; 2.07 A; A/B=535-860. DR PDB; 3BJC; X-ray; 2.00 A; A=1-875. DR PDB; 3HC8; X-ray; 1.79 A; A=536-657, A=682-858. DR PDB; 3HDZ; X-ray; 1.80 A; A=536-657, A=682-858. DR PDB; 3JWQ; X-ray; 2.87 A; A/B/C/D=535-786, A/B/C/D=827-860. DR PDB; 3JWR; X-ray; 2.99 A; A/B=535-786, A/B=827-860. DR PDB; 3LFV; X-ray; 2.80 A; A/B=98-518. DR PDB; 3MF0; X-ray; 3.10 A; A/B=89-518. DR PDB; 3SHY; X-ray; 2.65 A; A=535-860. DR PDB; 3SHZ; X-ray; 2.45 A; A=535-860. DR PDB; 3SIE; X-ray; 1.93 A; A/B=535-860. DR PDB; 3TGE; X-ray; 1.96 A; A=534-656, A=682-858. DR PDB; 3TGG; X-ray; 1.91 A; A=534-660, A=662-858. DR PDB; 4G2W; X-ray; 2.28 A; A=535-860. DR PDB; 4G2Y; X-ray; 2.40 A; A=535-860. DR PDB; 4I9Z; X-ray; 2.08 A; A=535-860. DR PDB; 4IA0; X-ray; 2.17 A; A=535-860. DR PDB; 4MD6; X-ray; 2.00 A; A=535-860. DR PDB; 4OEW; X-ray; 2.44 A; A=535-860. DR PDB; 4OEX; X-ray; 2.14 A; A=535-860. DR PDB; 5JO3; X-ray; 1.49 A; B=534-858. DR PDB; 5ZZ2; X-ray; 2.60 A; A=535-860. DR PDB; 6ACB; X-ray; 2.80 A; A=535-860. DR PDB; 6IWI; X-ray; 2.15 A; A=535-860. DR PDB; 6L6E; X-ray; 1.92 A; A=536-861. DR PDB; 6VBI; X-ray; 2.30 A; A/B=535-859. DR PDB; 7FAQ; X-ray; 2.20 A; A=527-875. DR PDB; 7FAR; X-ray; 2.40 A; A=527-875. DR PDB; 8W4S; X-ray; 1.85 A; A=535-860. DR PDB; 8W4T; X-ray; 2.20 A; A=535-860. DR PDBsum; 1RKP; -. DR PDBsum; 1T9R; -. DR PDBsum; 1T9S; -. DR PDBsum; 1TBF; -. DR PDBsum; 1UDT; -. DR PDBsum; 1UDU; -. DR PDBsum; 1UHO; -. DR PDBsum; 1XOZ; -. DR PDBsum; 1XP0; -. DR PDBsum; 2CHM; -. DR PDBsum; 2H40; -. DR PDBsum; 2H42; -. DR PDBsum; 2H44; -. DR PDBsum; 2XSS; -. DR PDBsum; 3B2R; -. DR PDBsum; 3BJC; -. DR PDBsum; 3HC8; -. DR PDBsum; 3HDZ; -. DR PDBsum; 3JWQ; -. DR PDBsum; 3JWR; -. DR PDBsum; 3LFV; -. DR PDBsum; 3MF0; -. DR PDBsum; 3SHY; -. DR PDBsum; 3SHZ; -. DR PDBsum; 3SIE; -. DR PDBsum; 3TGE; -. DR PDBsum; 3TGG; -. DR PDBsum; 4G2W; -. DR PDBsum; 4G2Y; -. DR PDBsum; 4I9Z; -. DR PDBsum; 4IA0; -. DR PDBsum; 4MD6; -. DR PDBsum; 4OEW; -. DR PDBsum; 4OEX; -. DR PDBsum; 5JO3; -. DR PDBsum; 5ZZ2; -. DR PDBsum; 6ACB; -. DR PDBsum; 6IWI; -. DR PDBsum; 6L6E; -. DR PDBsum; 6VBI; -. DR PDBsum; 7FAQ; -. DR PDBsum; 7FAR; -. DR PDBsum; 8W4S; -. DR PDBsum; 8W4T; -. DR AlphaFoldDB; O76074; -. DR SMR; O76074; -. DR BioGRID; 114205; 13. DR DIP; DIP-46287N; -. DR IntAct; O76074; 6. DR STRING; 9606.ENSP00000347046; -. DR BindingDB; O76074; -. DR ChEMBL; CHEMBL1827; -. DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine. DR DrugBank; DB08729; 5-ethoxy-4-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)thiophene-2-sulfonamide. DR DrugBank; DB06237; Avanafil. DR DrugBank; DB00201; Caffeine. DR DrugBank; DB00975; Dipyridamole. DR DrugBank; DB06246; Exisulind. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB03597; gamma-Glutamyl[S-(2-iodobenzyl)cysteinyl]glycine. DR DrugBank; DB01972; Guanosine-5'-Monophosphate. DR DrugBank; DB09282; Molsidomine. DR DrugBank; DB05415; OSI-461. DR DrugBank; DB01113; Papaverine. DR DrugBank; DB00203; Sildenafil. DR DrugBank; DB00820; Tadalafil. DR DrugBank; DB00277; Theophylline. DR DrugBank; DB09283; Trapidil. DR DrugBank; DB06267; Udenafil. DR DrugBank; DB00862; Vardenafil. DR DrugCentral; O76074; -. DR GuidetoPHARMACOLOGY; 1304; -. DR iPTMnet; O76074; -. DR PhosphoSitePlus; O76074; -. DR BioMuta; PDE5A; -. DR EPD; O76074; -. DR jPOST; O76074; -. DR MassIVE; O76074; -. DR MaxQB; O76074; -. DR PaxDb; 9606-ENSP00000347046; -. DR PeptideAtlas; O76074; -. DR ProteomicsDB; 50374; -. [O76074-1] DR ProteomicsDB; 50375; -. [O76074-2] DR Pumba; O76074; -. DR Antibodypedia; 1386; 234 antibodies from 36 providers. DR DNASU; 8654; -. DR Ensembl; ENST00000264805.9; ENSP00000264805.5; ENSG00000138735.16. [O76074-2] DR Ensembl; ENST00000354960.8; ENSP00000347046.3; ENSG00000138735.16. [O76074-1] DR GeneID; 8654; -. DR KEGG; hsa:8654; -. DR MANE-Select; ENST00000354960.8; ENSP00000347046.3; NM_001083.4; NP_001074.2. DR UCSC; uc003idf.4; human. [O76074-1] DR AGR; HGNC:8784; -. DR CTD; 8654; -. DR DisGeNET; 8654; -. DR GeneCards; PDE5A; -. DR HGNC; HGNC:8784; PDE5A. DR HPA; ENSG00000138735; Low tissue specificity. DR MIM; 603310; gene. DR neXtProt; NX_O76074; -. DR OpenTargets; ENSG00000138735; -. DR PharmGKB; PA33132; -. DR VEuPathDB; HostDB:ENSG00000138735; -. DR eggNOG; KOG3689; Eukaryota. DR GeneTree; ENSGT00940000155475; -. DR InParanoid; O76074; -. DR OMA; RDAYKHE; -. DR OrthoDB; 5479253at2759; -. DR PhylomeDB; O76074; -. DR TreeFam; TF316499; -. DR BRENDA; 3.1.4.35; 2681. DR PathwayCommons; O76074; -. DR Reactome; R-HSA-418457; cGMP effects. DR Reactome; R-HSA-445355; Smooth Muscle Contraction. DR Reactome; R-HSA-9013422; RHOBTB1 GTPase cycle. DR SignaLink; O76074; -. DR SIGNOR; O76074; -. DR UniPathway; UPA00763; UER00748. DR BioGRID-ORCS; 8654; 11 hits in 1157 CRISPR screens. DR ChiTaRS; PDE5A; human. DR EvolutionaryTrace; O76074; -. DR GeneWiki; CGMP-specific_phosphodiesterase_type_5; -. DR GenomeRNAi; 8654; -. DR Pharos; O76074; Tclin. DR PRO; PR:O76074; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; O76074; Protein. DR Bgee; ENSG00000138735; Expressed in calcaneal tendon and 151 other cell types or tissues. DR ExpressionAtlas; O76074; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB. DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; NAS:UniProtKB. DR GO; GO:0030553; F:cGMP binding; TAS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0046069; P:cGMP catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0055118; P:negative regulation of cardiac muscle contraction; IEA:Ensembl. DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl. DR GO; GO:0048599; P:oocyte development; IEA:Ensembl. DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IEA:Ensembl. DR GO; GO:0060282; P:positive regulation of oocyte development; IEA:Ensembl. DR GO; GO:0010749; P:regulation of nitric oxide mediated signal transduction; IEA:Ensembl. DR GO; GO:0055119; P:relaxation of cardiac muscle; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0042098; P:T cell proliferation; IEA:Ensembl. DR CDD; cd00077; HDc; 1. DR DisProt; DP01244; -. DR Gene3D; 3.30.450.40; -; 2. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1. DR InterPro; IPR003018; GAF. DR InterPro; IPR029016; GAF-like_dom_sf. DR InterPro; IPR003607; HD/PDEase_dom. DR InterPro; IPR023088; PDEase. DR InterPro; IPR002073; PDEase_catalytic_dom. DR InterPro; IPR036971; PDEase_catalytic_dom_sf. DR InterPro; IPR023174; PDEase_CS. DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR PANTHER; PTHR11347:SF230; HIGH AFFINITY CGMP-SPECIFIC 3',5'-CYCLIC PHOSPHODIESTERASE 9A; 1. DR Pfam; PF01590; GAF; 2. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00065; GAF; 2. DR SMART; SM00471; HDc; 1. DR SUPFAM; SSF55781; GAF domain-like; 2. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. DR Genevisible; O76074; HS. PE 1: Evidence at protein level; KW 3D-structure; Allosteric enzyme; Alternative splicing; cGMP; cGMP-binding; KW Hydrolase; Metal-binding; Nucleotide-binding; Phosphoprotein; KW Reference proteome; Repeat; Zinc. FT CHAIN 1..875 FT /note="cGMP-specific 3',5'-cyclic phosphodiesterase" FT /id="PRO_0000198823" FT DOMAIN 164..314 FT /note="GAF 1" FT DOMAIN 346..503 FT /note="GAF 2" FT DOMAIN 536..860 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 1..29 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 78..102 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 7..27 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 78..99 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 613 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 617 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:12955149, FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R, FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF" FT BINDING 653 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:12955149, FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R, FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF" FT BINDING 654 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:12955149" FT BINDING 654 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:12955149, FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R, FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF" FT BINDING 764 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:12955149, FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R, FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF" FT BINDING 817 FT /ligand="3',5'-cyclic GMP" FT /ligand_id="ChEBI:CHEBI:57746" FT /evidence="ECO:0000269|PubMed:12955149" FT MOD_RES 102 FT /note="Phosphoserine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..49 FT /note="MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKA -> FT MLPFGDK (in isoform PDE5A2)" FT /evidence="ECO:0000303|PubMed:9714779, ECO:0000303|Ref.4, FT ECO:0000303|Ref.5" FT /id="VSP_004591" FT VARIANT 93 FT /note="A -> V (in dbSNP:rs3733526)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:9642111, ECO:0000269|PubMed:9714779, FT ECO:0000269|PubMed:9716380, ECO:0000269|Ref.4" FT /id="VAR_027775" FT VARIANT 181 FT /note="S -> A (in dbSNP:rs17051276)" FT /id="VAR_027776" FT MUTAGEN 767 FT /note="A->N: Changes substrate selectivity from FT cGMP-specific to dual cAMP and cGMP binding and hydrolysis; FT when associated with Y-775 and Y-853." FT /evidence="ECO:0000269|PubMed:15260978" FT MUTAGEN 775 FT /note="Q->Y: Changes substrate selectivity from FT cGMP-specific to dual cAMP and cGMP binding and hydrolysis; FT when associated with N-767 and Y-853." FT /evidence="ECO:0000269|PubMed:15260978" FT MUTAGEN 853 FT /note="W->Y: Changes substrate selectivity from FT cGMP-specific to dual cAMP and cGMP binding and hydrolysis; FT when associated with N-767 and Y-775." FT /evidence="ECO:0000269|PubMed:15260978" FT CONFLICT 159 FT /note="I -> V (in Ref. 9; AAP31235)" FT /evidence="ECO:0000305" FT CONFLICT 310 FT /note="C -> G (in Ref. 9; AAP31235)" FT /evidence="ECO:0000305" FT CONFLICT 381 FT /note="S -> F (in Ref. 9; AAP31235)" FT /evidence="ECO:0000305" FT CONFLICT 406 FT /note="K -> R (in Ref. 9; AAP31235)" FT /evidence="ECO:0000305" FT CONFLICT 642 FT /note="E -> G (in Ref. 4; BAA81667)" FT /evidence="ECO:0000305" FT HELIX 103..106 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 115..117 FT /evidence="ECO:0007829|PDB:3LFV" FT TURN 118..120 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 121..124 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 148..160 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 165..177 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 182..192 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 198..205 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 208..210 FT /evidence="ECO:0007829|PDB:3MF0" FT STRAND 213..218 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 221..224 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 228..236 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 240..243 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 254..259 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 266..272 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 278..287 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 299..340 FT /evidence="ECO:0007829|PDB:3LFV" FT TURN 342..345 FT /evidence="ECO:0007829|PDB:3MF0" FT HELIX 346..362 FT /evidence="ECO:0007829|PDB:2XSS" FT STRAND 365..372 FT /evidence="ECO:0007829|PDB:2XSS" FT STRAND 374..376 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 379..387 FT /evidence="ECO:0007829|PDB:2XSS" FT TURN 388..390 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 391..393 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 400..403 FT /evidence="ECO:0007829|PDB:2XSS" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:2XSS" FT HELIX 410..418 FT /evidence="ECO:0007829|PDB:2XSS" FT STRAND 422..425 FT /evidence="ECO:0007829|PDB:2XSS" FT TURN 427..429 FT /evidence="ECO:0007829|PDB:2XSS" FT STRAND 431..433 FT /evidence="ECO:0007829|PDB:3LFV" FT STRAND 451..457 FT /evidence="ECO:0007829|PDB:2XSS" FT STRAND 461..471 FT /evidence="ECO:0007829|PDB:2XSS" FT TURN 476..478 FT /evidence="ECO:0007829|PDB:3LFV" FT HELIX 486..506 FT /evidence="ECO:0007829|PDB:2XSS" FT HELIX 535..545 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 551..554 FT /evidence="ECO:0007829|PDB:1TBF" FT TURN 555..557 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 568..581 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 584..587 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 592..604 FT /evidence="ECO:0007829|PDB:1TBF" FT TURN 606..608 FT /evidence="ECO:0007829|PDB:1T9R" FT STRAND 610..614 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 615..630 FT /evidence="ECO:0007829|PDB:1TBF" FT TURN 631..633 FT /evidence="ECO:0007829|PDB:1UHO" FT HELIX 635..637 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 640..652 FT /evidence="ECO:0007829|PDB:1TBF" FT TURN 653..656 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 662..667 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 671..675 FT /evidence="ECO:0007829|PDB:1TBF" FT STRAND 677..679 FT /evidence="ECO:0007829|PDB:6L6E" FT HELIX 680..694 FT /evidence="ECO:0007829|PDB:1TBF" FT TURN 700..703 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 706..722 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 725..740 FT /evidence="ECO:0007829|PDB:1TBF" FT STRAND 746..748 FT /evidence="ECO:0007829|PDB:1UDU" FT HELIX 749..764 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 766..769 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 772..796 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 803..805 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 807..812 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 813..823 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 825..835 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 837..839 FT /evidence="ECO:0007829|PDB:1TBF" FT HELIX 840..857 FT /evidence="ECO:0007829|PDB:1TBF" SQ SEQUENCE 875 AA; 99985 MW; 9E30C6C182F13388 CRC64; MERAGPSFGQ QRQQQQPQQQ KQQQRDQDSV EAWLDDHWDF TFSYFVRKAT REMVNAWFAE RVHTIPVCKE GIRGHTESCS CPLQQSPRAD NSAPGTPTRK ISASEFDRPL RPIVVKDSEG TVSFLSDSEK KEQMPLTPPR FDHDEGDQCS RLLELVKDIS SHLDVTALCH KIFLHIHGLI SADRYSLFLV CEDSSNDKFL ISRLFDVAEG STLEEVSNNC IRLEWNKGIV GHVAALGEPL NIKDAYEDPR FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE KDFAAYLAFC GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI LKKIAATIIS FMQVQKCTIF IVDEDCSDSF SSVFHMECEE LEKSSDTLTR EHDANKINYM YAQYVKNTME PLNIPDVSKD KRFPWTTENT GNVNQQCIRS LLCTPIKNGK KNKVIGVCQL VNKMEENTGK VKPFNRNDEQ FLEAFVIFCG LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL QSLAAAVVPS AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCRWIL SVKKNYRKNV AYHNWRHAFN TAQCMFAALK AGKIQNKLTD LEILALLIAA LSHDLDHRGV NNSYIQRSEH PLAQLYCHSI MEHHHFDQCL MILNSPGNQI LSGLSIEEYK TTLKIIKQAI LATDLALYIK RRGEFFELIR KNQFNLEDPH QKELFLAMLM TACDLSAITK PWPIQQRIAE LVATEFFDQG DRERKELNIE PTDLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF PLLDGCRKNR QKWQALAEQQ EKMLINGESG QAKRN //