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| | <StructureSection load='4n9l' size='340' side='right'caption='[[4n9l]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='4n9l' size='340' side='right'caption='[[4n9l]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4n9l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/"denitrobacillus_licheniformis"_(weigmann_1898)_verhoeven_1952 "denitrobacillus licheniformis" (weigmann 1898) verhoeven 1952]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N9L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N9L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4n9l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_licheniformis Bacillus licheniformis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N9L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N9L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DWZ:(2S,3R,4S)-4-{[(3S,5S)-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL}-2-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-METHYL-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>DWZ</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]] 2.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4n92|4n92]], [[4n9k|4n9k]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DWZ:(2S,3R,4S)-4-{[(3S,5S)-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL}-2-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-METHYL-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>DWZ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaP, penP, penP blaP ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1402 "Denitrobacillus licheniformis" (Weigmann 1898) Verhoeven 1952])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://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=4n9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n9l OCA], [https://pdbe.org/4n9l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n9l RCSB], [https://www.ebi.ac.uk/pdbsum/4n9l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n9l ProSAT]</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=4n9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n9l OCA], [https://pdbe.org/4n9l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n9l RCSB], [https://www.ebi.ac.uk/pdbsum/4n9l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n9l ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BLAC_BACLI BLAC_BACLI] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Beta-lactamase]] | + | [[Category: Bacillus licheniformis]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pan, X]] | + | [[Category: Pan X]] |
| - | [[Category: Wong, W]] | + | [[Category: Wong W]] |
| - | [[Category: Zhao, Y]] | + | [[Category: Zhao Y]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-antibiotic complex]]
| + | |
| Structural highlights
Function
BLAC_BACLI
Publication Abstract from PubMed
Most class A beta-lactamases cannot hydrolyze carbapenem antibiotics effectively. The molecular mechanism of this catalytic inefficiency has been attributed to the unique stereochemistry of carbapenems, including their 6-alpha-hydroxyethyl side chain and the transition between two tautomeric states when bound at the active site. Previous studies have shown that the 6-alpha-hydroxyethyl side chain of carbapenems can interfere with catalysis by forming hydrogen bonds with the deacylation water molecule to reduce its nucleophilicity. Here our studies of a class A noncarbapenemase PenP demonstrate that substituting the general base residue Glu166 with Ser or other residues leads to a significant enhancement of the acylation kinetics by approximately 100-500 times toward carbapenems like meropenem. The structures of PenP and Glu166Ser both in apo form and in complex with meropenem reveal that Glu166 is critical for the formation of a hydrogen bonding network within the active site that locks Asn170 in an orientation to impose steric clash with the 6-alpha-hydroxyethyl side chain of meropenem. The Glu166Ser substitution weakens this network and enables Asn170 to adopt an alternative conformation to avoid steric clash and accommodate faster acylation kinetics. Furthermore, the weakened hydrogen bonding network caused by the Glu166Ser substitution allows the 6-alpha-hydroxyethyl moiety to adopt a catalytically favorable orientation as seen in class A carbapenemases. In summary, our data identify a previously unreported role of the universally conserved general base residue Glu166 in impeding the proper binding of carbapenems by restricting their 6-alpha-hydroxyethyl group.
Perturbing the General Base Residue Glu166 in the Active Site of Class A beta-Lactamase Leads to Enhanced Carbapenem Binding and Acylation.,Pan X, Wong WT, He Y, Jiang Y, Zhao Y Biochemistry. 2014 Aug 26;53(33):5414-23. doi: 10.1021/bi401609h. Epub 2014 Aug, 15. PMID:25020031[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pan X, Wong WT, He Y, Jiang Y, Zhao Y. Perturbing the General Base Residue Glu166 in the Active Site of Class A beta-Lactamase Leads to Enhanced Carbapenem Binding and Acylation. Biochemistry. 2014 Aug 26;53(33):5414-23. doi: 10.1021/bi401609h. Epub 2014 Aug, 15. PMID:25020031 doi:http://dx.doi.org/10.1021/bi401609h
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