6g9f: Difference between revisions

Latest revision as of 08:57, 5 February 2020

Structural basis for the inhibition of E. coli PBP2

Structural highlights

6g9f is a 1 chain structure with sequence from Eco57. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	NXL
Gene:	mrdA, pbpA, b0635, JW0630 (ECO57)
Activity:	Serine-type D-Ala-D-Ala carboxypeptidase, with EC number 3.4.16.4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MRDA_ECOLI] Catalyzes cross-linking of the peptidoglycan cell wall (PubMed:3009484). Responsible for the determination of the rod shape of the cell (PubMed:1103132). Is probably required for lateral peptidoglycan synthesis and maintenance of the correct diameter during lateral and centripetal growth (PubMed:12519203).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Penicillin-binding proteins (PBPs) are the targets of the beta-lactams, the most successful class of antibiotics ever developed against bacterial infections. Unfortunately, the worldwide and rapid spread of large spectrum beta-lactam resistance genes such as carbapenemases is detrimental to the use of antibiotics in this class. New potent PBP inhibitors are needed, especially compounds that resist beta-lactamase hydrolysis. Here we describe the structure of the E. coli PBP2 in its Apo form and upon its reaction with 2 diazabicyclo derivatives, avibactam and CPD4, a new potent PBP2 inhibitor. Examination of these structures shows that unlike avibactam, CPD4 can perform a hydrophobic stacking on Trp370 in the active site of E. coli PBP2. This result, together with sequence analysis, homology modeling, and SAR, allows us to propose CPD4 as potential starting scaffold to develop molecules active against a broad range of bacterial species at the top of the WHO priority list.

Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design.,Levy N, Bruneau JM, Le Rouzic E, Bonnard D, Le Strat F, Caravano A, Chevreuil F, Barbion J, Chasset S, Ledoussal B, Moreau F, Ruff M J Med Chem. 2019 May 9;62(9):4742-4754. doi: 10.1021/acs.jmedchem.9b00338. Epub, 2019 Apr 26. PMID:30995398^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Spratt BG. Distinct penicillin binding proteins involved in the division, elongation, and shape of Escherichia coli K12. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2999-3003. PMID:1103132
↑ Den Blaauwen T, Aarsman ME, Vischer NO, Nanninga N. Penicillin-binding protein PBP2 of Escherichia coli localizes preferentially in the lateral wall and at mid-cell in comparison with the old cell pole. Mol Microbiol. 2003 Jan;47(2):539-47. PMID:12519203
↑ Ishino F, Park W, Tomioka S, Tamaki S, Takase I, Kunugita K, Matsuzawa H, Asoh S, Ohta T, Spratt BG, et al.. Peptidoglycan synthetic activities in membranes of Escherichia coli caused by overproduction of penicillin-binding protein 2 and rodA protein. J Biol Chem. 1986 May 25;261(15):7024-31. PMID:3009484
↑ Levy N, Bruneau JM, Le Rouzic E, Bonnard D, Le Strat F, Caravano A, Chevreuil F, Barbion J, Chasset S, Ledoussal B, Moreau F, Ruff M. Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design. J Med Chem. 2019 May 9;62(9):4742-4754. doi: 10.1021/acs.jmedchem.9b00338. Epub, 2019 Apr 26. PMID:30995398 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b00338

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OCA

[1] Spratt BG. Distinct penicillin binding proteins involved in the division, elongation, and shape of Escherichia coli K12. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2999-3003. PMID:1103132

[2] Den Blaauwen T, Aarsman ME, Vischer NO, Nanninga N. Penicillin-binding protein PBP2 of Escherichia coli localizes preferentially in the lateral wall and at mid-cell in comparison with the old cell pole. Mol Microbiol. 2003 Jan;47(2):539-47. PMID:12519203

[3] Ishino F, Park W, Tomioka S, Tamaki S, Takase I, Kunugita K, Matsuzawa H, Asoh S, Ohta T, Spratt BG, et al.. Peptidoglycan synthetic activities in membranes of Escherichia coli caused by overproduction of penicillin-binding protein 2 and rodA protein. J Biol Chem. 1986 May 25;261(15):7024-31. PMID:3009484

[4] Levy N, Bruneau JM, Le Rouzic E, Bonnard D, Le Strat F, Caravano A, Chevreuil F, Barbion J, Chasset S, Ledoussal B, Moreau F, Ruff M. Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design. J Med Chem. 2019 May 9;62(9):4742-4754. doi: 10.1021/acs.jmedchem.9b00338. Epub, 2019 Apr 26. PMID:30995398 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b00338

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[2]

[3]

[4]

@@ Line 3: / Line 3: @@
 <StructureSection load='6g9f' size='340' side='right'caption='[[6g9f]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6g9f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G9F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G9F FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6g9f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Eco57 Eco57]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G9F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G9F FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mrdA, pbpA, b0635, JW0630 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83334 ECO57])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6g9f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g9f OCA], [http://pdbe.org/6g9f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g9f RCSB], [http://www.ebi.ac.uk/pdbsum/6g9f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g9f ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MRDA_ECO57 MRDA_ECO57]] Catalyzes cross-linking of the peptidoglycan cell wall.
+[[http://www.uniprot.org/uniprot/MRDA_ECOLI MRDA_ECOLI]] Catalyzes cross-linking of the peptidoglycan cell wall (PubMed:3009484). Responsible for the determination of the rod shape of the cell (PubMed:1103132). Is probably required for lateral peptidoglycan synthesis and maintenance of the correct diameter during lateral and centripetal growth (PubMed:12519203).<ref>PMID:1103132</ref> <ref>PMID:12519203</ref> <ref>PMID:3009484</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 6g9f" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Penicillin-binding protein 3D structures|Penicillin-binding protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Eco57]]
 [[Category: Large Structures]]
 [[Category: Serine-type D-Ala-D-Ala carboxypeptidase]]

6g9f: Difference between revisions

Latest revision as of 08:57, 5 February 2020

Structural basis for the inhibition of E. coli PBP2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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