9q0b
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==CTX-M-15 WT in complex with BLIP E73W== | |
| + | <StructureSection load='9q0b' size='340' side='right'caption='[[9q0b]], [[Resolution|resolution]] 1.58Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9q0b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Streptomyces_clavuligerus Streptomyces clavuligerus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9Q0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Q0B FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58Å</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=9q0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9q0b OCA], [https://pdbe.org/9q0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9q0b RCSB], [https://www.ebi.ac.uk/pdbsum/9q0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9q0b ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BLC15_ECO25 BLC15_ECO25] Extended-spectrum beta-lactamase (ESBL) which confers resistance to penicillins, as well as first, second, third and fourth-generation cephalosporins (PubMed:11470367, PubMed:28069651, PubMed:29941650, PubMed:34310213, PubMed:35515906, PubMed:35563620). Has cefotaxime- and ceftazidime-hydrolyzing activity (PubMed:28069651, PubMed:29941650, PubMed:35515906). Inactive against the carbapenem antibiotics, imipenem, meropenem and ertapenem (PubMed:11470367, PubMed:29941650).<ref>PMID:11470367</ref> <ref>PMID:28069651</ref> <ref>PMID:29941650</ref> <ref>PMID:34310213</ref> <ref>PMID:35515906</ref> <ref>PMID:35563620</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | beta-lactamase enzymes inactivate beta-lactam antibiotics, leading to drug resistance. The beta-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor of beta-lactamases, with inhibition constants (K(i)) ranging from picomolar to micromolar values. For example, BLIP inhibits CTX-M-14 beta-lactamase with a K(i) of 330 nM while the K(i) for CTX-M-15 is 3 nM, despite CTX-M-14 and CTX-M-15 sharing 83% sequence identity. We used a genetic screen to identify a BLIP mutant, E73W, that potently inhibited CTX-M-14. Subsequent purification and testing of BLIP E73W revealed it is a potent, broad-spectrum inhibitor of class A beta-lactamases. We determined structures of BLIP E73W in complex with the CTX-M-14, CTX-M-15, and TEM-1 beta-lactamases to investigate the basis of the broad-spectrum inhibition. Previous structures of BLIP in complex with several class-A beta-lactamases revealed that beta-lactamase active site residue Tyr105 is found in an altered rotamer conformation. Also, in the case of the BLIP/CTX-M-15 complex, an altered conformation of the active site 103-106 loop is observed. In contrast, the BLIP E73W/beta-lactamase complexes did not show the altered conformations of Tyr105 or the 103-106 loop. Instead, the mutant's mechanism involves BLIP Trp73 trapping Tyr105 against the wall of the active site in a similar conformation as in the apo-enzyme. Interestingly, the E73W mutant binds the apo-enzyme conformation in all of the BLIP E73W/beta-lactamase complexes. Binding to the apo-enzyme conformation, which is expected to be highly populated in solution, as well as enhanced hydrophobic interactions of Trp73 with beta-lactamases are possible explanations for the high potency and broad-spectrum inhibition. | ||
| - | + | A beta-lactamase inhibitory protein mutant displays high potency and a broad inhibition profile due to an altered binding mode with beta-lactamases.,Rivera P, Lu S, Ngango D, Sankaran B, Venkataram Prasad BV, Palzkill T J Biol Chem. 2025 Oct 22:110850. doi: 10.1016/j.jbc.2025.110850. PMID:41135675<ref>PMID:41135675</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9q0b" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: Palzkill | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| + | [[Category: Escherichia coli]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Streptomyces clavuligerus]] | ||
| + | [[Category: Lu S]] | ||
| + | [[Category: Palzkill T]] | ||
| + | [[Category: Prasad BVV]] | ||
| + | [[Category: Rivera P]] | ||
| + | [[Category: Sankaran B]] | ||
Current revision
CTX-M-15 WT in complex with BLIP E73W
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