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| | ==Crystal structure of P99 beta-lactamase in complex with a penicillin derivative MPC-1== | | ==Crystal structure of P99 beta-lactamase in complex with a penicillin derivative MPC-1== |
| - | <StructureSection load='5xhr' size='340' side='right' caption='[[5xhr]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='5xhr' size='340' side='right'caption='[[5xhr]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5xhr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"aerobacter_cloacae"_(jordan_1890)_bergey_et_al._1923 "aerobacter cloacae" (jordan 1890) bergey et al. 1923]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XHR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XHR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5xhr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterobacter_cloacae Enterobacter cloacae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XHR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PXH:(2~{R},4~{S})-5,5-dimethyl-2-[(2~{S},3~{R})-3-oxidanyl-1-oxidanylidene-5-thiophen-2-yl-pentan-2-yl]-1,3-thiazolidine-4-carboxylic+acid'>PXH</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=550 "Aerobacter cloacae" (Jordan 1890) Bergey et al. 1923])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PXH:(2~{R},4~{S})-5,5-dimethyl-2-[(2~{S},3~{R})-3-oxidanyl-1-oxidanylidene-5-thiophen-2-yl-pentan-2-yl]-1,3-thiazolidine-4-carboxylic+acid'>PXH</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xhr OCA], [https://pdbe.org/5xhr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xhr RCSB], [https://www.ebi.ac.uk/pdbsum/5xhr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xhr ProSAT]</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=5xhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xhr OCA], [http://pdbe.org/5xhr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xhr RCSB], [http://www.ebi.ac.uk/pdbsum/5xhr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xhr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AMPC_ENTCL AMPC_ENTCL]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. | + | [https://www.uniprot.org/uniprot/AMPC_ENTCL AMPC_ENTCL] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5xhr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5xhr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Beta-lactamase]] | + | [[Category: Enterobacter cloacae]] |
| - | [[Category: Pan, X]] | + | [[Category: Large Structures]] |
| - | [[Category: Zhao, Y]] | + | [[Category: Pan X]] |
| - | [[Category: Hydrolase]] | + | [[Category: Zhao Y]] |
| Structural highlights
Function
AMPC_ENTCL This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
Publication Abstract from PubMed
Bacterial beta-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature beta-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D beta-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-alpha hydroxyethyl moiety to replace the original 6-beta aminoacyl group. MPC-1 selectively inhibits class C beta-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is approximately 2 to 5 times higher than that for clinically used beta-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A beta-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel beta-lactamase inhibitors.
Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C beta-Lactamases.,Pan X, He Y, Chen T, Chan KF, Zhao Y Antimicrob Agents Chemother. 2017 Nov 22;61(12). pii: AAC.01288-17. doi:, 10.1128/AAC.01288-17. Print 2017 Dec. PMID:28971874[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pan X, He Y, Chen T, Chan KF, Zhao Y. Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C beta-Lactamases. Antimicrob Agents Chemother. 2017 Nov 22;61(12). pii: AAC.01288-17. doi:, 10.1128/AAC.01288-17. Print 2017 Dec. PMID:28971874 doi:http://dx.doi.org/10.1128/AAC.01288-17
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