ID PDE5A_BOVIN Reviewed; 865 AA. AC Q28156; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 165. DE RecName: Full=cGMP-specific 3',5'-cyclic phosphodiesterase; DE EC=3.1.4.35 {ECO:0000250|UniProtKB:O76074}; DE AltName: Full=cGMP-binding cGMP-specific phosphodiesterase; DE Short=CGB-PDE; GN Name=PDE5A; Synonyms=PDE5; OS Bos taurus (Bovine). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; OC Bovinae; Bos. OX NCBI_TaxID=9913; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 4-16; 39-55; 90-101; RP 127-138; 390-409 AND 531-539. RC TISSUE=Lung; RX PubMed=8226796; DOI=10.1016/s0021-9258(18)41607-9; RA McAllister-Lucas L.M., Sonnenburg W.K., Kadlecek A., Seger D., Trong H.L., RA Colbran J.L., Thomas M.K., Walsh K.A., Francis S.H., Corbin J.D., RA Beavo J.A.; RT "The structure of a bovine lung cGMP-binding, cGMP-specific RT phosphodiesterase deduced from a cDNA clone."; RL J. Biol. Chem. 268:22863-22873(1993). RN [2] RP METAL-BINDING. RX PubMed=8077192; DOI=10.1016/s0021-9258(17)31669-1; RA Francis S.H., Colbran J.L., McAllister-Lucas L.M., Corbin J.D.; RT "Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific RT phosphodiesterase suggest that it is a zinc hydrolase."; RL J. Biol. Chem. 269:22477-22480(1994). RN [3] RP FUNCTION, AND MUTAGENESIS OF ASP-289 AND ASP-478. RX PubMed=8530505; DOI=10.1074/jbc.270.51.30671; RA McAllister-Lucas L.M., Haik T.L., Colbran J.L., Sonnenburg W.K., Seger D., RA Turko I.V., Beavo J.A., Francis S.H., Corbin J.D.; RT "An essential aspartic acid at each of two allosteric cGMP-binding sites of RT a cGMP-specific phosphodiesterase."; RL J. Biol. Chem. 270:30671-30679(1995). RN [4] RP MUTAGENESIS OF ASN-276; LYS-277; ASP-289 AND GLU-290. RX PubMed=8703039; DOI=10.1074/jbc.271.36.22240; RA Turko I.V., Haik T.L., McAllister-Lucas L.M., Burns F., Francis S.H., RA Corbin J.D.; RT "Identification of key amino acids in a conserved cGMP-binding site of RT cGMP-binding phosphodiesterases. A putative NKXnD motif for cGMP binding."; RL J. Biol. Chem. 271:22240-22244(1996). RN [5] RP PHOSPHORYLATION, AND MUTAGENESIS OF ASP-289 AND ASP-478. RX PubMed=9445376; DOI=10.1042/bj3290505; RA Turko I.V., Francis S.H., Corbin J.D.; RT "Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific RT phosphodiesterase (PDE5) is required for its phosphorylation."; RL Biochem. J. 329:505-510(1998). 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:8530505). Specifically regulates nitric-oxide-generated cGMP CC (By similarity). {ECO:0000250|UniProtKB:O76074, CC ECO:0000269|PubMed:8530505}. 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:0000250|UniProtKB:O76074}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958; CC Evidence={ECO:0000250|UniProtKB:O76074}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:O76074}; 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:0000250|UniProtKB:O76074}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:O76074}; 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:0000250|UniProtKB:O76074}; CC -!- ACTIVITY REGULATION: Most potently inhibited by zaprinast and CC dipyridamole. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from CC 3',5'-cyclic GMP: step 1/1. 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. Phosphorylation by PRKG1 leads to its activation (By CC similarity). {ECO:0000250}. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC {ECO:0000305}. 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; L16545; AAB00990.1; -; mRNA. DR RefSeq; NP_776842.1; NM_174417.2. DR PDB; 3JAB; EM; 11.00 A; C/O=525-850. DR PDB; 3JBQ; EM; 11.00 A; B/F=525-850. DR PDBsum; 3JAB; -. DR PDBsum; 3JBQ; -. DR AlphaFoldDB; Q28156; -. DR EMDB; EMD-6258; -. DR SMR; Q28156; -. DR BioGRID; 159263; 1. DR STRING; 9913.ENSBTAP00000014479; -. DR BindingDB; Q28156; -. DR ChEMBL; CHEMBL3478; -. DR DrugCentral; Q28156; -. DR iPTMnet; Q28156; -. DR PaxDb; 9913-ENSBTAP00000014479; -. DR Ensembl; ENSBTAT00000014479.5; ENSBTAP00000014479.4; ENSBTAG00000024888.5. DR GeneID; 281972; -. DR KEGG; bta:281972; -. DR CTD; 8654; -. DR VEuPathDB; HostDB:ENSBTAG00000024888; -. DR VGNC; VGNC:32678; PDE5A. DR eggNOG; KOG3689; Eukaryota. DR GeneTree; ENSGT00940000155475; -. DR HOGENOM; CLU_006980_0_2_1; -. DR InParanoid; Q28156; -. DR OrthoDB; 5479253at2759; -. DR TreeFam; TF316499; -. DR Reactome; R-BTA-418457; cGMP effects. DR Reactome; R-BTA-445355; Smooth Muscle Contraction. DR Reactome; R-BTA-9013422; RHOBTB1 GTPase cycle. DR UniPathway; UPA00763; UER00748. DR PRO; PR:Q28156; -. DR Proteomes; UP000009136; Chromosome 6. DR Bgee; ENSBTAG00000024888; Expressed in spiral colon and 109 other cell types or tissues. DR ExpressionAtlas; Q28156; baseline and differential. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISS:AgBase. DR GO; GO:0030553; F:cGMP binding; ISS:AgBase. DR GO; GO:0004112; F:cyclic-nucleotide phosphodiesterase activity; ISS:AgBase. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0046069; P:cGMP catabolic process; ISS:AgBase. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR CDD; cd00077; HDc; 1. 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. PE 1: Evidence at protein level; KW 3D-structure; Allosteric enzyme; cGMP; cGMP-binding; KW Direct protein sequencing; Hydrolase; Magnesium; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat; Zinc. FT CHAIN 1..865 FT /note="cGMP-specific 3',5'-cyclic phosphodiesterase" FT /id="PRO_0000198821" FT DOMAIN 154..304 FT /note="GAF 1" FT DOMAIN 336..493 FT /note="GAF 2" FT DOMAIN 526..850 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT ACT_SITE 603 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 607 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O76074" FT BINDING 643 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O76074" FT BINDING 644 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250|UniProtKB:O76074" FT BINDING 644 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O76074" FT BINDING 754 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O76074" FT BINDING 807 FT /ligand="3',5'-cyclic GMP" FT /ligand_id="ChEBI:CHEBI:57746" FT /evidence="ECO:0000250|UniProtKB:O76074" FT MOD_RES 92 FT /note="Phosphoserine" FT /evidence="ECO:0000255" FT MUTAGEN 276 FT /note="N->A: Decreased cGMP-binding; no change in catalytic FT activity." FT /evidence="ECO:0000269|PubMed:8703039" FT MUTAGEN 277 FT /note="K->A: Decreased cGMP-binding; no change in catalytic FT activity." FT /evidence="ECO:0000269|PubMed:8703039" FT MUTAGEN 277 FT /note="K->R: Slight increase in cGMP-binding." FT /evidence="ECO:0000269|PubMed:8703039" FT MUTAGEN 289 FT /note="D->A: Decreased cGMP-binding; no change in catalytic FT activity." FT /evidence="ECO:0000269|PubMed:8530505, FT ECO:0000269|PubMed:8703039, ECO:0000269|PubMed:9445376" FT MUTAGEN 289 FT /note="D->N: Increased cGMP-binding; no change in catalytic FT activity." FT /evidence="ECO:0000269|PubMed:8530505, FT ECO:0000269|PubMed:8703039, ECO:0000269|PubMed:9445376" FT MUTAGEN 290 FT /note="E->A: No change in cGMP-binding." FT /evidence="ECO:0000269|PubMed:8703039" FT MUTAGEN 478 FT /note="D->A: Increased cGMP-binding; no change in catalytic FT activity. Phosphorylated at lower concentrations of cGMP." FT /evidence="ECO:0000269|PubMed:8530505, FT ECO:0000269|PubMed:9445376" SQ SEQUENCE 865 AA; 98627 MW; 2FF7144B2990B4F7 CRC64; MERAGPGSAR PQQQWDQDSV EAWLDDHWDF TFSYFVRKGT REMVNAWFAE RVHTIPVCKE GIKGHTESCS CPLQPSPRAE SSVPGTPTRK ISASEFDRPL RPIVIKDSEG TVSFLSDSDK KEQMPLTSPR FDNDEGDQCS RLLELVKDIS SHLDVTALCH KIFLHIHGLI SADRYSLFLV CEDSSNDKFL ISRLFDVAEG STLEEASNNC IRLEWNKGIV GHVAAFGEPL NIKDAYEDPR FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE KDFAAYLAFC GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI LKKIAATIIS FMQVQKCTIF IVDEDCSDSF SSVFHMECEE LEKSSDTLTR ERDANRINYM YAQYVKNTME PLNIPDVSKD KRFPWTNENM GNINQQCIRS LLCTPIKNGK KNKVIGVCQL VNKMEETTGK VKAFNRNDEQ FLEAFVIFCG LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL QSLAAAVVPS AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCKWIL SVKKNYRKNV AYHNWRHAFN TAQCMFAALK AGKIQKRLTD LEILALLIAA LSHDLDHRGV NNSYIQRSEH PLAQLYCHSI MEHHHFDQCL MILNSPGNQI LSGLSIEEYK TTLKIIKQAI LATDLALYIK RRGEFFELIM KNQFNLEDPH QKELFLAMLM TACDLSAITK PWPIQQRIAE LVATEFFDQG DRERKELNIE PADLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF PLLDGCRKNR QKWQALAEQQ EKTLINGESS QTKRN //