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PDBsum entry 1a8t
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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1a8t

 

 

 

 

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Contents
Protein chains
230 a.a. *
Ligands
061
Metals
_ZN ×4
Waters ×183
* Residue conservation analysis
PDB id:
1a8t
Name: Hydrolase
Title: Metallo-beta-lactamase in complex with l-159,061
Structure: Metallo-beta-lactamase. Chain: a, b. Synonym: class b beta-lactamase. Engineered: yes. Mutation: yes
Source: Bacteroides fragilis. Organism_taxid: 817. Strain: tal3636. Variant: clinical isolate. Gene: ccra. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.55Å     R-factor:   0.181     R-free:   0.319
Authors: P.M.D.Fitzgerald,J.H.Toney,N.Grover,D.Vanderwall
Key ref: J.H.Toney et al. (1998). Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase. Chem Biol, 5, 185-196. PubMed id: 9545432
Date:
23-Mar-98     Release date:   14-Oct-98    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P25910  (BLAB_BACFG) -  Metallo-beta-lactamase type 2 from Bacteroides fragilis
Seq:
Struc: 		249 a.a.
230 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.5.2.6  - beta-lactamase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Penicillin Biosynthesis and Metabolism
      Reaction: a beta-lactam + H2O = a substituted beta-amino acid
      Cofactor: Zn(2+)

 

 
Chem Biol 5:185-196 (1998)
PubMed id: 9545432  
 
 
Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.
J.H.Toney, P.M.Fitzgerald, N.Grover-Sharma, S.H.Olson, W.J.May, J.G.Sundelof, D.E.Vanderwall, K.A.Cleary, S.K.Grant, J.K.Wu, J.W.Kozarich, D.L.Pompliano, G.G.Hammond.
 
  ABSTRACT  
 
BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20394454 C.Bebrone, P.Lassaux, L.Vercheval, J.S.Sohier, A.Jehaes, E.Sauvage, and M.Galleni (2010).
Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
  Drugs, 70, 651-679.  
20121112 P.Oelschlaeger, N.Ai, K.T.Duprez, W.J.Welsh, and J.H.Toney (2010).
Evolving carbapenemases: can medicinal chemists advance one step ahead of the coming storm?
  J Med Chem, 53, 3013-3027.  
20065329 S.M.Drawz, and R.A.Bonomo (2010).
Three decades of beta-lactamase inhibitors.
  Clin Microbiol Rev, 23, 160-201.  
19505232 P.A.Sanchez, J.H.Toney, J.D.Thomas, and J.M.Berger (2009).
A sensitive coupled HPLC/electrospray mass spectrometry assay for SPM-1 metallo-beta-lactamase inhibitors.
  Assay Drug Dev Technol, 7, 170-179.  
18449576 A.Badarau, and M.I.Page (2008).
Loss of enzyme activity during turnover of the Bacillus cereus beta-lactamase catalysed hydrolysis of beta-lactams due to loss of zinc ion.
  J Biol Inorg Chem, 13, 919-928.  
18327330 L.M.Frija, I.V.Khmelinskii, C.Serpa, I.D.Reva, R.Fausto, and M.L.Cristiano (2008).
Photochemistry of 5-allyloxy-tetrazoles: steady-state and laser flash photolysis study.
  Org Biomol Chem, 6, 1046-1055.  
18528987 N.Sharma, Z.Hu, M.W.Crowder, and B.Bennett (2008).
Conformational changes in the metallo-beta-lactamase ImiS during the catalytic reaction: an EPR spectrokinetic study of Co(II)-spin label interactions.
  J Am Chem Soc, 130, 8215-8222.  
17623844 F.Simona, A.Magistrato, D.M.Vera, G.Garau, A.J.Vila, and P.Carloni (2007).
Protonation state and substrate binding to B2 metallo-beta-lactamase CphA from Aeromonas hydrofila.
  Proteins, 69, 595-605.  
17493872 G.D.Wright, and A.D.Sutherland (2007).
New strategies for combating multidrug-resistant bacteria.
  Trends Mol Med, 13, 260-267.  
16773613 G.Estiu, D.Suárez, and K.M.Merz (2006).
Quantum mechanical and molecular dynamics simulations of ureases and Zn beta-lactamases.
  J Comput Chem, 27, 1240-1262.  
15937993 J.Antony, J.P.Piquemal, and N.Gresh (2005).
Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry.
  J Comput Chem, 26, 1131-1147.  
16100733 S.Bräse, C.Gil, K.Knepper, and V.Zimmermann (2005).
Organic azides: an exploding diversity of a unique class of compounds.
  Angew Chem Int Ed Engl, 44, 5188-5240.  
15831827 T.R.Walsh, M.A.Toleman, L.Poirel, and P.Nordmann (2005).
Metallo-beta-lactamases: the quiet before the storm?
  Clin Microbiol Rev, 18, 306-325.  
15159411 P.S.Mercuri, I.García-Sáez, K.De Vriendt, I.Thamm, B.Devreese, J.Van Beeumen, O.Dideberg, G.M.Rossolini, J.M.Frère, and M.Galleni (2004).
Probing the specificity of the subclass B3 FEZ-1 metallo-beta-lactamase by site-directed mutagenesis.
  J Biol Chem, 279, 33630-33638.  
15140877 R.M.Rasia, and A.J.Vila (2004).
Structural determinants of substrate binding to Bacillus cereus metallo-beta-lactamase.
  J Biol Chem, 279, 26046-26051.  
15187432 W.Jin, Y.Arakawa, H.Yasuzawa, T.Taki, R.Hashiguchi, K.Mitsutani, A.Shoga, Y.Yamaguchi, H.Kurosaki, N.Shibata, M.Ohta, and M.Goto (2004).
Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group.
  Biol Pharm Bull, 27, 851-856.  
12724330 C.Damblon, M.Jensen, A.Ababou, I.Barsukov, C.Papamicael, C.J.Schofield, L.Olsen, R.Bauer, and G.C.Roberts (2003).
The inhibitor thiomandelic acid binds to both metal ions in metallo-beta-lactamase and induces positive cooperativity in metal binding.
  J Biol Chem, 278, 29240-29251.  
12725860 C.Moali, C.Anne, J.Lamotte-Brasseur, S.Groslambert, B.Devreese, J.Van Beeumen, M.Galleni, and J.M.Frère (2003).
Analysis of the importance of the metallo-beta-lactamase active site loop in substrate binding and catalysis.
  Chem Biol, 10, 319-329.  
12684522 I.García-Saez, J.Hopkins, C.Papamicael, N.Franceschini, G.Amicosante, G.M.Rossolini, M.Galleni, J.M.Frère, and O.Dideberg (2003).
The 1.5-A structure of Chryseobacterium meningosepticum zinc beta-lactamase in complex with the inhibitor, D-captopril.
  J Biol Chem, 278, 23868-23873.
PDB code: 1m2x
12824483 J.J.Huntley, W.Fast, S.J.Benkovic, P.E.Wright, and H.J.Dyson (2003).
Role of a solvent-exposed tryptophan in the recognition and binding of antibiotic substrates for a metallo-beta-lactamase.
  Protein Sci, 12, 1368-1375.  
12578382 S.Siemann, A.J.Clarke, T.Viswanatha, and G.I.Dmitrienko (2003).
Thiols as classical and slow-binding inhibitors of IMP-1 and other binuclear metallo-beta-lactamases.
  Biochemistry, 42, 1673-1683.  
11876827 A.L.Carenbauer, J.D.Garrity, G.Periyannan, R.B.Yates, and M.W.Crowder (2002).
Probing substrate binding to metallo-beta-lactamase L1 from Stenotrophomonas maltophilia by using site-directed mutagenesis.
  BMC Biochem, 3, 4.  
12019104 D.J.Payne, J.A.Hueso-Rodríguez, H.Boyd, N.O.Concha, C.A.Janson, M.Gilpin, J.H.Bateson, C.Cheever, N.L.Niconovich, S.Pearson, S.Rittenhouse, D.Tew, E.Díez, P.Pérez, J.De La Fuente, M.Rees, and A.Rivera-Sagredo (2002).
Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.
  Antimicrob Agents Chemother, 46, 1880-1886.
PDB codes: 1hlk 1kr3
12022865 D.Suárez, E.N.Brothers, and K.M.Merz (2002).
Insights into the structure and dynamics of the dinuclear zinc beta-lactamase site from Bacteroides fragilis.
  Biochemistry, 41, 6615-6630.  
12395427 D.Suárez, N.Díaz, and K.M.Merz (2002).
Molecular dynamics simulations of the dinuclear zinc-beta-lactamase from Bacteroides fragilis complexed with imipenem.
  J Comput Chem, 23, 1587-1600.  
12210153 J.Antony, N.Gresh, L.Olsen, L.Hemmingsen, C.J.Schofield, and R.Bauer (2002).
Binding of D- and L-captopril inhibitors to metallo-beta-lactamase studied by polarizable molecular mechanics and quantum mechanics.
  J Comput Chem, 23, 1281-1296.  
12546840 P.W.Taylor, P.D.Stapleton, and J.Paul Luzio (2002).
New ways to treat bacterial infections.
  Drug Discov Today, 7, 1086-1091.  
12121917 S.Siemann, D.P.Evanoff, L.Marrone, A.J.Clarke, T.Viswanatha, and G.I.Dmitrienko (2002).
N-arylsulfonyl hydrazones as inhibitors of IMP-1 metallo-beta-lactamase.
  Antimicrob Agents Chemother, 46, 2450-2457.  
11119652 A.I.Su, D.M.Lorber, G.S.Weston, W.A.Baase, B.W.Matthews, and B.K.Shoichet (2001).
Docking molecules by families to increase the diversity of hits in database screens: computational strategy and experimental evaluation.
  Proteins, 42, 279-293.  
11432752 A.Zervosen, M.H.Valladares, B.Devreese, C.Prosperi-Meys, H.W.Adolph, P.S.Mercuri, M.Vanhove, G.Amicosante, J.van Beeumen, J.M.Frère, and M.Galleni (2001).
Inactivation of Aeromonas hydrophila metallo-beta-lactamase by cephamycins and moxalactam.
  Eur J Biochem, 268, 3840-3850.  
11181339 M.Galleni, J.Lamotte-Brasseur, G.M.Rossolini, J.Spencer, O.Dideberg, and J.M.Frère (2001).
Standard numbering scheme for class B beta-lactamases.
  Antimicrob Agents Chemother, 45, 660-663.  
11060675 D.J.Payne, W.Du, and J.H.Bateson (2000).
beta-Lactamase epidemiology and the utility of established and novel beta-lactamase inhibitors.
  Expert Opin Investig Drugs, 9, 247-261.  
11063572 J.J.Huntley, S.D.Scrofani, M.J.Osborne, P.E.Wright, and H.J.Dyson (2000).
Dynamics of the metallo-beta-lactamase from Bacteroides fragilis in the presence and absence of a tight-binding inhibitor.
  Biochemistry, 39, 13356-13364.  
11271821 K.Nesmĕrák, M.Pospísek, I.Nĕmec, K.Waisser, and J.Gabriel (2000).
Antifungal properties of substituted 1-phenyl-5-mercaptotetrazoles and their oxidation product, 5-bis-(1-phenyltetrazolyl)disulfide.
  Folia Microbiol (Praha), 45, 138-142.  
11498375 M.G.Page (2000).
b-Lactamase inhibitors.
  Drug Resist Updat, 3, 109-125.  
11036013 N.Franceschini, B.Caravelli, J.D.Docquier, M.Galleni, J.M.Frère, G.Amicosante, and G.M.Rossolini (2000).
Purification and biochemical characterization of the VIM-1 metallo-beta-lactamase.
  Antimicrob Agents Chemother, 44, 3003-3007.  
10757977 N.O.Concha, C.A.Janson, P.Rowling, S.Pearson, C.A.Cheever, B.P.Clarke, C.Lewis, M.Galleni, J.M.Frère, D.J.Payne, J.H.Bateson, and S.S.Abdel-Meguid (2000).
Crystal structure of the IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor: binding determinants of a potent, broad-spectrum inhibitor.
  Biochemistry, 39, 4288-4298.
PDB codes: 1dd6 1ddk
10904248 Y.T.Tan, D.J.Tillett, and I.A.McKay (2000).
Molecular strategies for overcoming antibiotic resistance in bacteria.
  Mol Med Today, 6, 309-314.  
  10518728 G.G.Hammond, J.L.Huber, M.L.Greenlee, J.B.Laub, K.Young, L.L.Silver, J.M.Balkovec, K.D.Pryor, J.K.Wu, B.Leiting, D.L.Pompliano, and J.H.Toney (1999).
Inhibition of IMP-1 metallo-beta-lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives.
  FEMS Microbiol Lett, 179, 289-296.  
10509927 J.H.Toney, K.A.Cleary, G.G.Hammond, X.Yuan, W.J.May, S.M.Hutchins, W.T.Ashton, and D.E.Vanderwall (1999).
Structure-activity relationships of biphenyl tetrazoles as metallo-beta-lactamase inhibitors.
  Bioorg Med Chem Lett, 9, 2741-2746.  
10498206 M.L.Greenlee, J.B.Laub, J.M.Balkovec, M.L.Hammond, G.G.Hammond, D.L.Pompliano, and J.H.Epstein-Toney (1999).
Synthesis and SAR of thioester and thiol inhibitors of IMP-1 metallo-beta-lactamase.
  Bioorg Med Chem Lett, 9, 2549-2554.  
  10508031 R.Nagano, Y.Adachi, H.Imamura, K.Yamada, T.Hashizume, and H.Morishima (1999).
Carbapenem derivatives as potential inhibitors of various beta-lactamases, including class B metallo-beta-lactamases.
  Antimicrob Agents Chemother, 43, 2497-2503.  
10508665 Z.Wang, W.Fast, A.M.Valentine, and S.J.Benkovic (1999).
Metallo-beta-lactamase: structure and mechanism.
  Curr Opin Chem Biol, 3, 614-622.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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