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PDBsum entry 1vqq
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Biosynthetic protein PDB id
1vqq

 

 

 

 

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Contents
Protein chains
635 a.a. *
Metals
_CL ×4
_CD ×7
Waters ×508
* Residue conservation analysis
PDB id:
1vqq
Name: Biosynthetic protein
Title: Structure of penicillin binding protein 2a from methicillin resistant staphylococcus aureus strain 27r at 1.80 a resolution.
Structure: Penicillin-binding protein meca, low-affinity. Chain: a, b. Fragment: residues 23-668. Synonym: saupbp2a. Engineered: yes. Mutation: yes
Source: Staphylococcus aureus. Organism_taxid: 1280. Gene: meca. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.237     R-free:   0.274
Authors: D.Lim,N.C.J.Strynadka
Key ref:
D.Lim and N.C.Strynadka (2002). Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol, 9, 870-876. PubMed id: 12389036
Date:
17-Dec-04     Release date:   28-Dec-04    
Supersedes: 1mwx
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q93IC2  (Q93IC2_STAAU) -  Penicillin-binding protein 2' from Staphylococcus aureus
Seq:
Struc: 		 
Seq:
Struc: 		668 a.a.
635 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.4.1.129  - Transferred entry: 2.4.99.28.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Peptidoglycan Biosynthesis (Part 3)
      Reaction: [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)](n)- di-trans,octa-cis-undecaprenyl diphosphate + beta-D-GlcNAc-(1->4)- Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-di-trans,octa- cis-undecaprenyl diphosphate = [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D- Glu-L-Lys-D-Ala-D-Ala)](n+1)-di-trans-octa-cis-undecaprenyl diphosphate + di-trans,octa-cis-undecaprenyl diphosphate + H+
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)](n)- di-trans,octa-cis-undecaprenyl diphosphate
 + beta-D-GlcNAc-(1->4)- Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-di-trans,octa- cis-undecaprenyl diphosphate
 = [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D- Glu-L-Lys-D-Ala-D-Ala)](n+1)-di-trans-octa-cis-undecaprenyl diphosphate
 + di-trans,octa-cis-undecaprenyl diphosphate
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Key reference    
 
 
Nat Struct Biol 9:870-876 (2002)
PubMed id: 12389036  
 
 
Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus.
D.Lim, N.C.Strynadka.
 
  ABSTRACT  
 
The multiple antibiotic resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) has become a major clinical problem worldwide. The key determinant of the broad-spectrum beta-lactam resistance in MRSA strains is the penicillin-binding protein 2a (PBP2a). Because of its low affinity for beta-lactams, PBP2a provides transpeptidase activity to allow cell wall synthesis at beta-lactam concentrations that inhibit the beta-lactam-sensitive PBPs normally produced by S. aureus. The crystal structure of a soluble derivative of PBP2a has been determined to 1.8 A resolution and provides the highest resolution structure for a high molecular mass PBP. Additionally, structures of the acyl-PBP complexes of PBP2a with nitrocefin, penicillin G and methicillin allow, for the first time, a comparison of an apo and acylated resistant PBP. An analysis of the PBP2a active site in these forms reveals the structural basis of its resistance and identifies features in newly developed beta-lactams that are likely important for high affinity binding.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21115457 D.Biek, I.A.Critchley, T.A.Riccobene, and D.A.Thye (2010).
Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity.
  J Antimicrob Chemother, 65, iv9-i16.  
  20640225 D.S.Johnson, E.Weerapana, and B.F.Cravatt (2010).
Strategies for discovering and derisking covalent, irreversible enzyme inhibitors.
  Future Med Chem, 2, 949-964.  
20071556 D.T.Nguyen, E.Yeh, S.Perry, R.F.Luo, B.A.Pinsky, B.P.Lee, D.Sisodiya, E.J.Baron, and N.Banaei (2010).
Real-time PCR testing for mecA reduces vancomycin usage and length of hospitalization for patients infected with methicillin-sensitive staphylococci.
  J Clin Microbiol, 48, 785-790.  
20194704 K.Kosowska-Shick, P.L.McGhee, and P.C.Appelbaum (2010).
Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.
  Antimicrob Agents Chemother, 54, 1670-1677.  
19932622 S.A.Adediran, D.Cabaret, J.F.Lohier, M.Wakselman, and R.F.Pratt (2010).
Substituted aryl malonamates as new serine beta-lactamase substrates: structure-activity studies.
  Bioorg Med Chem, 18, 282-291.  
18986991 A.J.Powell, J.Tomberg, A.M.Deacon, R.A.Nicholas, and C.Davies (2009).
Crystal Structures of Penicillin-binding Protein 2 from Penicillin-susceptible and -resistant Strains of Neisseria gonorrhoeae Reveal an Unexpectedly Subtle Mechanism for Antibiotic Resistance.
  J Biol Chem, 284, 1202-1212.
PDB codes: 3equ 3eqv
19470504 L.I.Llarrull, J.F.Fisher, and S.Mobashery (2009).
Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge.
  Antimicrob Agents Chemother, 53, 4051-4063.  
19173709 M.Ender, B.Berger-Bächi, and N.McCallum (2009).
A novel DNA-binding protein modulating methicillin resistance in Staphylococcus aureus.
  BMC Microbiol, 9, 15.  
19490203 R.A.Stein, R.M.Goetz, and G.M.Ganea (2009).
Ceftobiprole: a new beta-lactam antibiotic.
  Int J Clin Pract, 63, 930-943.  
18582062 A.Villegas-Estrada, M.Lee, D.Hesek, S.B.Vakulenko, and S.Mobashery (2008).
Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: potent inhibition of PBP 2a by two anti-MRSA beta-lactam antibiotics.
  J Am Chem Soc, 130, 9212-9213.  
18248419 A.Zapun, C.Contreras-Martel, and T.Vernet (2008).
Penicillin-binding proteins and beta-lactam resistance.
  FEMS Microbiol Rev, 32, 361-385.  
18784364 E.J.Hayhurst, L.Kailas, J.K.Hobbs, and S.J.Foster (2008).
Cell wall peptidoglycan architecture in Bacillus subtilis.
  Proc Natl Acad Sci U S A, 105, 14603-14608.  
18602645 E.Sauvage, A.J.Powell, J.Heilemann, H.R.Josephine, P.Charlier, C.Davies, and R.F.Pratt (2008).
Crystal structures of complexes of bacterial DD-peptidases with peptidoglycan-mimetic ligands: the substrate specificity puzzle.
  J Mol Biol, 381, 383-393.
PDB codes: 2vgj 2vgk 3beb 3bec
18266856 E.Sauvage, F.Kerff, M.Terrak, J.A.Ayala, and P.Charlier (2008).
The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis.
  FEMS Microbiol Rev, 32, 234-258.  
18321228 M.Bassetti, E.Righi, and C.Viscoli (2008).
Novel beta-lactam antibiotics and inhibitor combinations.
  Expert Opin Investig Drugs, 17, 285-296.  
18083809 M.J.Noto, B.N.Kreiswirth, A.B.Monk, and G.L.Archer (2008).
Gene acquisition at the insertion site for SCCmec, the genomic island conferring methicillin resistance in Staphylococcus aureus.
  J Bacteriol, 190, 1276-1283.  
18318877 P.Moreillon (2008).
New and emerging treatment of Staphylococcus aureus infections in the hospital setting.
  Clin Microbiol Infect, 14, 32-41.  
19166431 R.A.Stein (2008).
A new antibiotic: lessons and perspectives.
  Int J Clin Pract, 62, 1836-1837.  
18378703 R.Banerjee, M.Gretes, L.Basuino, N.Strynadka, and H.F.Chambers (2008).
In vitro selection and characterization of ceftobiprole-resistant methicillin-resistant Staphylococcus aureus.
  Antimicrob Agents Chemother, 52, 2089-2096.  
18337244 S.Lemaire, C.Fuda, F.Van Bambeke, P.M.Tulkens, and S.Mobashery (2008).
Restoration of susceptibility of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics by acidic pH: role of penicillin-binding protein PBP 2a.
  J Biol Chem, 283, 12769-12776.  
18519723 T.Koga, N.Masuda, M.Kakuta, E.Namba, C.Sugihara, and T.Fukuoka (2008).
Potent in vitro activity of tomopenem (CS-023) against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
  Antimicrob Agents Chemother, 52, 2849-2854.  
17554049 H.Bierne, and P.Cossart (2007).
Listeria monocytogenes surface proteins: from genome predictions to function.
  Microbiol Mol Biol Rev, 71, 377-397.  
17483219 L.I.Salzberg, and J.D.Helmann (2007).
An antibiotic-inducible cell wall-associated protein that protects Bacillus subtilis from autolysis.
  J Bacteriol, 189, 4671-4680.  
17466017 M.Levisson, J.van der Oost, and S.W.Kengen (2007).
Characterization and structural modeling of a new type of thermostable esterase from Thermotoga maritima.
  FEBS J, 274, 2832-2842.  
17925392 X.Fan, Y.Liu, D.Smith, L.Konermann, K.W.Siu, and D.Golemi-Kotra (2007).
Diversity of penicillin-binding proteins. Resistance factor FmtA of Staphylococcus aureus.
  J Biol Chem, 282, 35143-35152.  
16751607 A.L.Lovering, L.De Castro, D.Lim, and N.C.Strynadka (2006).
Structural analysis of an "open" form of PBP1B from Streptococcus pneumoniae.
  Protein Sci, 15, 1701-1709.
PDB code: 2fff
16952957 B.Zuber, M.Haenni, T.Ribeiro, K.Minnig, F.Lopes, P.Moreillon, and J.Dubochet (2006).
Granular layer in the periplasmic space of gram-positive bacteria and fine structures of Enterococcus gallinarum and Streptococcus gordonii septa revealed by cryo-electron microscopy of vitreous sections.
  J Bacteriol, 188, 6652-6660.  
16459335 C.Fuda, D.Hesek, M.Lee, W.Heilmayer, R.Novak, S.B.Vakulenko, and S.Mobashery (2006).
Mechanistic basis for the action of new cephalosporin antibiotics effective against methicillin- and vancomycin-resistant Staphylococcus aureus.
  J Biol Chem, 281, 10035-10041.  
16524423 D.M.Livermore (2006).
Can beta-lactams be re-engineered to beat MRSA?
  Clin Microbiol Infect, 12, 11-16.  
16881035 F.von Nussbaum, M.Brands, B.Hinzen, S.Weigand, and D.Häbich (2006).
Antibacterial natural products in medicinal chemistry--exodus or revival?
  Angew Chem Int Ed Engl, 45, 5072-5129.  
  16582476 M.K.Safo, T.P.Ko, F.N.Musayev, Q.Zhao, A.H.Wang, and G.L.Archer (2006).
Structure of the MecI repressor from Staphylococcus aureus in complex with the cognate DNA operator of mec.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 320-324.
PDB code: 2d45
16911039 P.Macheboeuf, C.Contreras-Martel, V.Job, O.Dideberg, and A.Dessen (2006).
Penicillin binding proteins: key players in bacterial cell cycle and drug resistance processes.
  FEMS Microbiol Rev, 30, 673-691.  
16537437 S.O.Meroueh, K.Z.Bencze, D.Hesek, M.Lee, J.F.Fisher, T.L.Stemmler, and S.Mobashery (2006).
Three-dimensional structure of the bacterial cell wall peptidoglycan.
  Proc Natl Acad Sci U S A, 103, 4404-4409.  
16428405 V.R.Matias, and T.J.Beveridge (2006).
Native cell wall organization shown by cryo-electron microscopy confirms the existence of a periplasmic space in Staphylococcus aureus.
  J Bacteriol, 188, 1011-1021.  
16145104 A.M.Bressler, T.Williams, E.E.Culler, W.Zhu, D.Lonsway, J.B.Patel, and F.S.Nolte (2005).
Correlation of penicillin Binding protein 2a detection with oxacillin resistance in Staphylococcus aureus and discovery of a novel penicillin binding protein 2a mutation.
  J Clin Microbiol, 43, 4541-4544.  
15673741 A.M.Hujer, M.Kania, T.Gerken, V.E.Anderson, J.D.Buynak, X.Ge, P.Caspers, M.G.Page, L.B.Rice, and R.A.Bonomo (2005).
Structure-activity relationships of different beta-lactam antibiotics against a soluble form of Enterococcus faecium PBP5, a type II bacterial transpeptidase.
  Antimicrob Agents Chemother, 49, 612-618.  
16166526 A.Severin, S.W.Wu, K.Tabei, and A.Tomasz (2005).
High-level (beta)-lactam resistance and cell wall synthesis catalyzed by the mecA homologue of Staphylococcus sciuri introduced into Staphylococcus aureus.
  J Bacteriol, 187, 6651-6658.  
15596446 C.Morlot, L.Pernot, A.Le Gouellec, A.M.Di Guilmi, T.Vernet, O.Dideberg, and A.Dessen (2005).
Crystal structure of a peptidoglycan synthesis regulatory factor (PBP3) from Streptococcus pneumoniae.
  J Biol Chem, 280, 15984-15991.
PDB code: 1xp4
16339737 D.J.Scheffers, and M.G.Pinho (2005).
Bacterial cell wall synthesis: new insights from localization studies.
  Microbiol Mol Biol Rev, 69, 585-607.  
15987687 E.Sauvage, R.Herman, S.Petrella, C.Duez, F.Bouillenne, J.M.Frère, and P.Charlier (2005).
Crystal structure of the Actinomadura R39 DD-peptidase reveals new domains in penicillin-binding proteins.
  J Biol Chem, 280, 31249-31256.
PDB codes: 1w79 1w8q 1w8y
15728879 H.F.Chambers (2005).
Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.
  Antimicrob Agents Chemother, 49, 884-888.  
16129657 M.S.Wilke, A.L.Lovering, and N.C.Strynadka (2005).
Beta-lactam antibiotic resistance: a current structural perspective.
  Curr Opin Microbiol, 8, 525-533.  
15637155 P.Macheboeuf, A.M.Di Guilmi, V.Job, T.Vernet, O.Dideberg, and A.Dessen (2005).
Active site restructuring regulates ligand recognition in class A penicillin-binding proteins.
  Proc Natl Acad Sci U S A, 102, 577-582.
PDB codes: 2bg1 2bg3 2bg4 2uwx 2uwy 2xd1
16272704 T.Kuzuhara, M.Suganuma, H.Tsuge, and H.Fujiki (2005).
Presence of a motif conserved between Helicobacter pylori TNF-alpha inducing protein (Tipalpha) and penicillin-binding proteins.
  Biol Pharm Bull, 28, 2133-2137.  
15561827 A.Severin, S.W.Wu, K.Tabei, and A.Tomasz (2004).
Penicillin-binding protein 2 is essential for expression of high-level vancomycin resistance and cell wall synthesis in vancomycin-resistant Staphylococcus aureus carrying the enterococcal vanA gene complex.
  Antimicrob Agents Chemother, 48, 4566-4573.  
15489425 B.A.Dmitriev, F.V.Toukach, O.Holst, E.T.Rietschel, and S.Ehlers (2004).
Tertiary structure of Staphylococcus aureus cell wall murein.
  J Bacteriol, 186, 7141-7148.  
15226303 C.Fuda, M.Suvorov, S.B.Vakulenko, and S.Mobashery (2004).
The basis for resistance to beta-lactam antibiotics by penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus.
  J Biol Chem, 279, 40802-40806.  
15158255 G.Mallorquí-Fernández, A.Marrero, S.García-Piquè, R.García-Castellanos, and F.X.Gomis-Rüth (2004).
Staphylococcal methicillin resistance: fine focus on folds and functions.
  FEMS Microbiol Lett, 235, 1-8.  
15504859 J.Vouillamoz, J.M.Entenza, P.Hohl, and P.Moreillon (2004).
LB11058, a new cephalosporin with high penicillin-binding protein 2a affinity and activity in experimental endocarditis due to homogeneously methicillin-resistant Staphylococcus aureus.
  Antimicrob Agents Chemother, 48, 4322-4327.  
15355966 L.Loschi, S.J.Brokx, T.L.Hills, G.Zhang, M.G.Bertero, A.L.Lovering, J.H.Weiner, and N.C.Strynadka (2004).
Structural and biochemical identification of a novel bacterial oxidoreductase.
  J Biol Chem, 279, 50391-50400.
PDB codes: 1xdq 1xdy
14734544 L.Pernot, L.Chesnel, A.Le Gouellec, J.Croizé, T.Vernet, O.Dideberg, and A.Dessen (2004).
A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics.
  J Biol Chem, 279, 16463-16470.
PDB code: 1rp5
15322076 M.S.Wilke, T.L.Hills, H.Z.Zhang, H.F.Chambers, and N.C.Strynadka (2004).
Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus.
  J Biol Chem, 279, 47278-47287.
PDB codes: 1xa1 1xa7
14736870 S.Hanique, M.L.Colombo, E.Goormaghtigh, P.Soumillion, J.M.Frère, and B.Joris (2004).
Evidence of an intramolecular interaction between the two domains of the BlaR1 penicillin receptor during the signal transduction.
  J Biol Chem, 279, 14264-14272.  
14742194 Y.Katayama, H.Z.Zhang, and H.F.Chambers (2004).
PBP 2a mutations producing very-high-level resistance to beta-lactams.
  Antimicrob Agents Chemother, 48, 453-459.  
12867450 A.M.Di Guilmi, A.Dessen, O.Dideberg, and T.Vernet (2003).
The glycosyltransferase domain of penicillin-binding protein 2a from Streptococcus pneumoniae catalyzes the polymerization of murein glycan chains.
  J Bacteriol, 185, 4418-4423.  
  12727914 F.D.Lowy (2003).
Antimicrobial resistance: the example of Staphylococcus aureus.
  J Clin Invest, 111, 1265-1273.  
12706985 H.F.Chambers (2003).
Solving staphylococcal resistance to beta-lactams.
  Trends Microbiol, 11, 145-148.  
12627955 N.Rhazi, P.Charlier, D.Dehareng, D.Engher, M.Vermeire, J.M.Frère, M.Nguyen-Distèche, and E.Fonzé (2003).
Catalytic mechanism of the Streptomyces K15 DD-transpeptidase/penicillin-binding protein probed by site-directed mutagenesis and structural analysis.
  Biochemistry, 42, 2895-2906.
PDB codes: 1es2 1es3 1es4 1j9m
12670537 S.Li, and R.W.Roberts (2003).
A novel strategy for in vitro selection of peptide-drug conjugates.
  Chem Biol, 10, 233-239.  
12472381 C.Giglione, and T.Meinnel (2002).
The situation on antimicrobial agents and chemotherapy in 2002: highlights of the 42nd ICAAC.
  Expert Opin Ther Targets, 6, 691-697.  
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 codes are shown on the right.

 

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