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Hydrolase PDB id
1jje
Jmol
Contents
Protein chains
220 a.a. *
Ligands
ACT ×2
BYS ×2
Metals
_ZN ×6
Waters ×184
* Residue conservation analysis
PDB id:
1jje
Name: Hydrolase
Title: Imp-1 metallo beta-lactamase from pseudomonas aeruginosa in with a biaryl succinic acid inhibitor (11)
Structure: Imp-1 metallo beta-lactamase. Chain: a, b. Fragment: metallo-beta-lactamase. Engineered: yes. Other_details: please note that the protein contains postra modification: atom cg of asn 26 is bound to atom n of gly 2 accounts for missing atoms listed in remark 470 and distort geometry reported for these residues.
Source: Pseudomonas aeruginosa. Organism_taxid: 287. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.80Å     R-factor:   0.201     R-free:   0.291
Authors: P.M.D.Fitzgerald,N.Sharma
Key ref:
J.H.Toney et al. (2001). Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-lactamase. J Biol Chem, 276, 31913-31918. PubMed id: 11390410 DOI: 10.1074/jbc.M104742200
Date:
04-Jul-01     Release date:   25-Jul-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q79MP6  (Q79MP6_PSEAE) -  Beta-lactamase
Seq:
Struc: 		246 a.a.
220 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     antibiotic catabolic process   1 term 
  Biochemical function     hydrolase activity     4 terms  

 

 
DOI no: 10.1074/jbc.M104742200 J Biol Chem 276:31913-31918 (2001)
PubMed id: 11390410  
 
 
Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-lactamase.
J.H.Toney, G.G.Hammond, P.M.Fitzgerald, N.Sharma, J.M.Balkovec, G.P.Rouen, S.H.Olson, M.L.Hammond, M.L.Greenlee, Y.D.Gao.
 
  ABSTRACT  
 
IMP-1 metallo-beta-lactamase (class B) is a plasmid-borne zinc metalloenzyme that efficiently hydrolyzes beta-lactam antibiotics, including carbapenems, rendering them ineffective. Because IMP-1 has been found in several clinically important carbapenem-resistant pathogens, there is a need for inhibitors of this enzyme that could protect broad spectrum antibiotics such as imipenem from hydrolysis and thus extend their utility. We have identified a series of 2,3-(S,S)-disubstituted succinic acids that are potent inhibitors of IMP-1. Determination of high resolution crystal structures and molecular modeling of succinic acid inhibitor complexes with IMP-1 has allowed an understanding of the potency, stereochemistry, and structure-activity relationships of these inhibitors.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Binding modes of compounds 2 (shown in cyan) and 3 (shown in red) docked into the IMP-1 active site complexed with compound 1. 		Figure 4.
Fig. 4. Binding modes of compound 8 docked into the active site of IMP-1 using the x-ray crystal structure of IMP-1 complexed with compound 1 (shown in cyan). The two most probable conformations of the S-isomer of compound 8 are shown in red and in yellow.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 31913-31918) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21536436 P.Vella, W.M.Hussein, E.W.Leung, D.Clayton, D.L.Ollis, N.Mitić, G.Schenk, and R.P.McGeary (2011).
The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening.
  Bioorg Med Chem Lett, 21, 3282-3285.  
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 ß-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.  
20305272 Y.Yamaguchi, N.Takashio, J.Wachino, Y.Yamagata, Y.Arakawa, K.Matsuda, and H.Kurosaki (2010).
Structure of metallo-beta-lactamase IND-7 from a Chryseobacterium indologenes clinical isolate at 1.65-A resolution.
  J Biochem, 147, 905-915.
PDB code: 3l6n
19553129 D.Minond, S.A.Saldanha, P.Subramaniam, M.Spaargaren, T.Spicer, J.R.Fotsing, T.Weide, V.V.Fokin, K.B.Sharpless, M.Galleni, C.Bebrone, P.Lassaux, and P.Hodder (2009).
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries.
  Bioorg Med Chem, 17, 5027-5037.  
19604476 E.E.Chufán, M.De, B.A.Eipper, R.E.Mains, and L.M.Amzel (2009).
Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme.
  Structure, 17, 965-973.
PDB codes: 3fvz 3fw0
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.  
18563261 B.M.Liénard, G.Garau, L.Horsfall, A.I.Karsisiotis, C.Damblon, P.Lassaux, C.Papamicael, G.C.Roberts, M.Galleni, O.Dideberg, J.M.Frère, and C.J.Schofield (2008).
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols.
  Org Biomol Chem, 6, 2282-2294.
PDB codes: 2qds 2qdt
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.  
16404761 J.Spencer, and T.R.Walsh (2006).
A new approach to the inhibition of metallo-beta-lactamases.
  Angew Chem Int Ed Engl, 45, 1022-1026.  
16713713 N.Selevsek, A.Tholey, E.Heinzle, B.M.Liénard, N.J.Oldham, C.J.Schofield, U.Heinz, H.W.Adolph, and J.M.Frère (2006).
Studies on ternary metallo-beta lactamase-inhibitor complexes using electrospray ionization mass spectrometry.
  J Am Soc Mass Spectrom, 17, 1000-1004.  
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.  
15668002 J.G.Moloughney, J.D Thomas, and J.H.Toney (2005).
Novel IMP-1 metallo-beta-lactamase inhibitors can reverse meropenem resistance in Escherichia coli expressing IMP-1.
  FEMS Microbiol Lett, 243, 65-71.  
16314577 M.H.Kim, W.C.Choi, H.O.Kang, J.S.Lee, B.S.Kang, K.J.Kim, Z.S.Derewenda, T.K.Oh, C.H.Lee, and J.K.Lee (2005).
The molecular structure and catalytic mechanism of a quorum-quenching N-acyl-L-homoserine lactone hydrolase.
  Proc Natl Acad Sci U S A, 102, 17606-17611.
PDB codes: 2br6 2btn
  16510987 N.Sharma, J.H.Toney, and P.M.Fitzgerald (2005).
Expression, purification, crystallization and preliminary X-ray analysis of Aeromonas hydrophilia metallo-beta-lactamase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 180-182.  
16172409 P.E.Tomatis, R.M.Rasia, L.Segovia, and A.J.Vila (2005).
Mimicking natural evolution in metallo-beta-lactamases through second-shell ligand mutations.
  Proc Natl Acad Sci U S A, 102, 13761-13766.  
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.  
14747990 M.Dal Peraro, A.J.Vila, and P.Carloni (2004).
Substrate binding to mononuclear metallo-beta-lactamase from Bacillus cereus.
  Proteins, 54, 412-423.  
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.  
  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.  
12736495 M.Goto, H.Yasuzawa, T.Higashi, Y.Yamaguchi, A.Kawanami, S.Mifune, H.Mori, H.Nakayama, K.Harada, and Y.Arakawa (2003).
Dependence of hydrolysis of beta-lactams with a zinc(II)-beta-lactamase produced from Serratia marcescens (IMP-1) on pH and concentration of zinc(II) ion: dissociation of Zn(II) from IMP-1 in acidic medium.
  Biol Pharm Bull, 26, 589-594.  
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.  
  11934488 B.J.Denny, P.A.Lambert, and P.W.West (2002).
The flavonoid galangin inhibits the L1 metallo-beta-lactamase from Stenotrophomonas maltophilia.
  FEMS Microbiol Lett, 208, 21-24.  
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.  
12384365 H.Mammeri, S.Bellais, and P.Nordmann (2002).
Chromosome-encoded beta-lactamases TUS-1 and MUS-1 from Myroides odoratus and Myroides odoratimimus (formerly Flavobacterium odoratum), new members of the lineage of molecular subclass B1 metalloenzymes.
  Antimicrob Agents Chemother, 46, 3561-3567.  
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.  
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.