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Protein

Metallo-beta-lactamase type 2

Gene

ccrA

Organism
Bacteroides fragilis
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Confers resistance to the different beta-lactams antibiotics (penicillin, cephalosporin and carbapenem) via the hydrolysis of the beta-lactam ring.3 Publications

Catalytic activityi

A beta-lactam + H2O = a substituted beta-amino acid.1 Publication

Cofactori

Zn2+8 PublicationsNote: Binds 2 Zn2+ ions per subunit. It can also bind Cd2+ and Co2+ to a lesser extend (PubMed:9416622).7 Publications

Enzyme regulationi

Competitively inhibited by 4-morpholineethanesulfonic acid (MES), SB236050 and biphenyl tetrazoles (BPTs) (PubMed:9578564, PubMed:9545432, PubMed:12019104). Also inhibited by chelating agents such as EDTA and 1,10-phenanthroline (PubMed:9712862). CcrA is not susceptible to inactivation by the beta-lactamase-blocking agents clavulanic acid or tazobactam (PubMed:2121094, PubMed:2110145).6 Publications

Kineticsi

Kcat is 225.7 sec(-1) for lactamase activity with nitrocefin as substrate (with zinc ions at pH 7 and 25 degrees Celsius). Kcat is 107.6 sec(-1) for lactamase activity with nitrocefin as substrate (with cobalt ions at pH 7 and 25 degrees Celsius).1 Publication

  1. KM=7.1 µM for nitrocefin (with zinc ions at pH 7 and 25 degrees Celsius)1 Publication
  2. KM=14 µM for nitrocefin (with cobalt ions at pH 7 and 25 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi99 – 991Zinc 1; via tele nitrogen7 Publications
    Metal bindingi101 – 1011Zinc 1; via pros nitrogen7 Publications
    Metal bindingi103 – 1031Zinc 26 Publications
    Metal bindingi162 – 1621Zinc 1; via tele nitrogen7 Publications
    Metal bindingi181 – 1811Zinc 26 Publications
    Binding sitei184 – 1841Substrate1 Publication
    Binding sitei193 – 1931Substrate; via amide nitrogen3 Publications
    Metal bindingi223 – 2231Zinc 2; via tele nitrogen6 Publications

    GO - Molecular functioni

    • beta-lactamase activity Source: UniProtKB
    • zinc ion binding Source: UniProtKB

    GO - Biological processi

    • antibiotic catabolic process Source: UniProtKB
    • response to antibiotic Source: UniProtKB-KW
    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Biological processi

    Antibiotic resistance

    Keywords - Ligandi

    Metal-binding, Zinc

    Enzyme and pathway databases

    SABIO-RKP25910.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Metallo-beta-lactamase type 2Curated (EC:3.5.2.61 Publication)
    Alternative name(s):
    B2 metallo-beta-lactamaseCurated
    Beta-lactamase II1 Publication
    Carbapenem and cephamycin resistance1 Publication
    Short name:
    CCRA1 Publication
    CephalosporinaseCurated
    Imipenem-cefoxitin hydrolyzing enzyme1 Publication
    Metallo-beta-lactamase type II1 Publication
    PenicillinaseCurated
    Zinc-requiring beta-lactamase1 Publication
    Gene namesi
    Name:ccrA1 Publication
    Synonyms:cfiA1 Publication
    OrganismiBacteroides fragilis
    Taxonomic identifieri817 [NCBI]
    Taxonomic lineageiBacteriaBacteroidetesBacteroidiaBacteroidalesBacteroidaceaeBacteroides

    Subcellular locationi

    • Periplasm 1 Publication

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Periplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi181 – 1811C → S: The overall structure of the mutant is the same as that of the wild-type, however the site of the second zinc ion is unoccupied. 1 Publication

    Chemistry

    ChEMBLiCHEMBL4840.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 1818Sequence analysis2 PublicationsAdd
    BLAST
    Chaini19 – 249231Metallo-beta-lactamase type 2PRO_0000016945Add
    BLAST

    Interactioni

    Subunit structurei

    Monomer.4 Publications

    Protein-protein interaction databases

    STRINGi457424.BFAG_03627.

    Chemistry

    BindingDBiP25910.

    Structurei

    Secondary structure

    1
    249
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi22 – 243Combined sources
    Beta strandi25 – 328Combined sources
    Beta strandi34 – 4613Combined sources
    Turni47 – 493Combined sources
    Beta strandi50 – 6112Combined sources
    Beta strandi64 – 696Combined sources
    Helixi74 – 8815Combined sources
    Beta strandi91 – 966Combined sources
    Beta strandi98 – 1014Combined sources
    Helixi102 – 1054Combined sources
    Helixi108 – 1136Combined sources
    Beta strandi117 – 1215Combined sources
    Helixi122 – 13110Combined sources
    Beta strandi137 – 14812Combined sources
    Beta strandi151 – 1566Combined sources
    Beta strandi161 – 1633Combined sources
    Beta strandi168 – 1703Combined sources
    Turni172 – 1743Combined sources
    Beta strandi176 – 1805Combined sources
    Turni199 – 2013Combined sources
    Helixi202 – 21211Combined sources
    Beta strandi217 – 2248Combined sources
    Helixi230 – 24617Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1A7TX-ray1.85A/B18-249[»]
    1A8TX-ray2.55A/B18-249[»]
    1HLKX-ray2.50A/B21-247[»]
    1KR3X-ray2.50A/B18-249[»]
    1ZNBX-ray1.85A/B18-249[»]
    2BMIX-ray2.00A/B18-249[»]
    2ZNBX-ray2.15A/B18-249[»]
    3ZNBX-ray2.70A/B18-249[»]
    4ZNBX-ray2.65A/B18-249[»]
    ProteinModelPortaliP25910.
    SMRiP25910. Positions 20-249.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP25910.

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiENOG4107YH7. Bacteria.
    ENOG410ZW82. LUCA.

    Family and domain databases

    Gene3Di3.60.15.10. 1 hit.
    InterProiIPR001018. Beta-lactamase_class-B_CS.
    IPR001279. Metallo-B-lactamas.
    [Graphical view]
    SMARTiSM00849. Lactamase_B. 1 hit.
    [Graphical view]
    SUPFAMiSSF56281. SSF56281. 1 hit.
    PROSITEiPS00743. BETA_LACTAMASE_B_1. 1 hit.
    PS00744. BETA_LACTAMASE_B_2. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P25910-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MKTVFILISM LFPVAVMAQK SVKISDDISI TQLSDKVYTY VSLAEIEGWG
    60 70 80 90 100
    MVPSNGMIVI NNHQAALLDT PINDAQTEML VNWVTDSLHA KVTTFIPNHW
    110 120 130 140 150
    HGDCIGGLGY LQRKGVQSYA NQMTIDLAKE KGLPVPEHGF TDSLTVSLDG
    160 170 180 190 200
    MPLQCYYLGG GHATDNIVVW LPTENILFGG CMLKDNQATS IGNISDADVT
    210 220 230 240
    AWPKTLDKVK AKFPSARYVV PGHGDYGGTE LIEHTKQIVN QYIESTSKP
    Length:249
    Mass (Da):27,257
    Last modified:May 1, 1992 - v1
    Checksum:i972B5A594DF5D40D
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M63556 Genomic DNA. Translation: AAA22904.1.
    M34831 Genomic DNA. Translation: AAA22907.1.
    PIRiA44999. A35263.
    RefSeqiWP_005808062.1. NZ_JPHS01000286.1.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M63556 Genomic DNA. Translation: AAA22904.1.
    M34831 Genomic DNA. Translation: AAA22907.1.
    PIRiA44999. A35263.
    RefSeqiWP_005808062.1. NZ_JPHS01000286.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1A7TX-ray1.85A/B18-249[»]
    1A8TX-ray2.55A/B18-249[»]
    1HLKX-ray2.50A/B21-247[»]
    1KR3X-ray2.50A/B18-249[»]
    1ZNBX-ray1.85A/B18-249[»]
    2BMIX-ray2.00A/B18-249[»]
    2ZNBX-ray2.15A/B18-249[»]
    3ZNBX-ray2.70A/B18-249[»]
    4ZNBX-ray2.65A/B18-249[»]
    ProteinModelPortaliP25910.
    SMRiP25910. Positions 20-249.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi457424.BFAG_03627.

    Chemistry

    BindingDBiP25910.
    ChEMBLiCHEMBL4840.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Phylogenomic databases

    eggNOGiENOG4107YH7. Bacteria.
    ENOG410ZW82. LUCA.

    Enzyme and pathway databases

    SABIO-RKP25910.

    Miscellaneous databases

    EvolutionaryTraceiP25910.

    Family and domain databases

    Gene3Di3.60.15.10. 1 hit.
    InterProiIPR001018. Beta-lactamase_class-B_CS.
    IPR001279. Metallo-B-lactamas.
    [Graphical view]
    SMARTiSM00849. Lactamase_B. 1 hit.
    [Graphical view]
    SUPFAMiSSF56281. SSF56281. 1 hit.
    PROSITEiPS00743. BETA_LACTAMASE_B_1. 1 hit.
    PS00744. BETA_LACTAMASE_B_2. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    1. "Cloning and sequencing of the class B beta-lactamase gene (ccrA) from Bacteroides fragilis TAL3636."
      Rasmussen B.A., Gluzman Y., Tally F.P.
      Antimicrob. Agents Chemother. 34:1590-1592(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, ENZYME REGULATION.
      Strain: TAL3636.
    2. "Escherichia coli chromosomal mutations that permit direct cloning of the Bacteroides fragilis metallo-beta-lactamase gene, ccrA."
      Rasmussen B.A., Gluzman Y., Tally F.P.
      Mol. Microbiol. 5:1211-1219(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION.
      Strain: TAL3636.
    3. "Sequencing the gene for an imipenem-cefoxitin-hydrolyzing enzyme (CfiA) from Bacteroides fragilis TAL2480 reveals strong similarity between CfiA and Bacillus cereus beta-lactamase II."
      Thompson J.S., Malamy M.H.
      J. Bacteriol. 172:2584-2593(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: TAL2480.
    4. "Purification, characterization, and kinetic studies of a soluble Bacteroides fragilis metallo-beta-lactamase that provides multiple antibiotic resistance."
      Wang Z., Benkovic S.J.
      J. Biol. Chem. 273:22402-22408(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, COFACTOR.
    5. "Crystal structure of the wide-spectrum binuclear zinc beta-lactamase from Bacteroides fragilis."
      Concha N.O., Rasmussen B.A., Bush K., Herzberg O.
      Structure 4:823-836(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 18-249 IN COMPLEX WITH ZINC IONS, COFACTOR.
    6. "Crystal structures of the cadmium- and mercury-substituted metallo-beta-lactamase from Bacteroides fragilis."
      Concha N.O., Rasmussen B.A., Bush K., Herzberg O.
      Protein Sci. 6:2671-2676(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 18-249 IN COMPLEX WITH ZINC IONS, COFACTOR.
    7. "X-ray structure of the ZnII beta-lactamase from Bacteroides fragilis in an orthorhombic crystal form."
      Carfi A., Duee E., Paul-Soto R., Galleni M., Frere J.M., Dideberg O.
      Acta Crystallogr. D 54:45-57(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 18-249 IN COMPLEX WITH ZINC IONS, COFACTOR, SUBUNIT.
    8. "Unanticipated inhibition of the metallo-beta-lactamase from Bacteroides fragilis by 4-morpholineethanesulfonic acid (MES): a crystallographic study at 1.85-A resolution."
      Fitzgerald P.M., Wu J.K., Toney J.H.
      Biochemistry 37:6791-6800(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 18-249 IN COMPLEX WITH SUBSTRATE ANALOG AND ZINC IONS, ENZYME REGULATION, COFACTOR, SUBUNIT.
    9. "Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase."
      Toney J.H., Fitzgerald P.M., Grover-Sharma N., Olson S.H., May W.J., Sundelof J.G., Vanderwall D.E., Cleary K.A., Grant S.K., Wu J.K., Kozarich J.W., Pompliano D.L., Hammond G.G.
      Chem. Biol. 5:185-196(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 18-249 IN COMPLEX WITH SUBSTRATE ANALOG AND ZINC IONS, ENZYME REGULATION, COFACTOR, SUBUNIT.
    10. "Structural consequences of the active site substitution Cys181 ==> Ser in metallo-beta-lactamase from Bacteroides fragilis."
      Li Z., Rasmussen B.A., Herzberg O.
      Protein Sci. 8:249-252(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 18-249 OF MUTANT SER-181 IN COMPLEX WITH ZINC IONS, COFACTOR, MUTAGENESIS OF CYS-181.
    11. Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 18-249 IN COMPLEX WITH SUBSTRATE ANALOG AND ZINC IONS, ENZYME REGULATION, COFACTOR, SUBUNIT.

    Entry informationi

    Entry nameiBLAB_BACFG
    AccessioniPrimary (citable) accession number: P25910
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 1, 1992
    Last sequence update: May 1, 1992
    Last modified: June 8, 2016
    This is version 102 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.