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==X-ray crystal structure of AmpC beta-lactamase with nanomolar inhibitor==
==X-ray crystal structure of AmpC beta-lactamase with nanomolar inhibitor==
<StructureSection load='6dpt' size='340' side='right' caption='[[6dpt]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
<StructureSection load='6dpt' size='340' side='right'caption='[[6dpt]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6dpt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DPT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DPT FirstGlance]. <br>
<table><tr><td colspan='2'>[[6dpt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DPT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H7M:3-chloro-2-hydroxy-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]phenyl}benzene-1-sulfonamide'>H7M</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]] 1.79&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H7M:3-chloro-2-hydroxy-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]phenyl}benzene-1-sulfonamide'>H7M</scene></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=6dpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dpt OCA], [http://pdbe.org/6dpt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dpt RCSB], [http://www.ebi.ac.uk/pdbsum/6dpt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dpt 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=6dpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dpt OCA], [https://pdbe.org/6dpt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dpt RCSB], [https://www.ebi.ac.uk/pdbsum/6dpt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dpt ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.  
[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC beta-lactamase (AmpC) and the D4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D4 dopamine receptor.
 
Ultra-large library docking for discovering new chemotypes.,Lyu J, Wang S, Balius TE, Singh I, Levit A, Moroz YS, O'Meara MJ, Che T, Algaa E, Tolmachova K, Tolmachev AA, Shoichet BK, Roth BL, Irwin JJ Nature. 2019 Feb;566(7743):224-229. doi: 10.1038/s41586-019-0917-9. Epub 2019 Feb, 6. PMID:30728502<ref>PMID:30728502</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dpt" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Beta-lactamase]]
[[Category: Escherichia coli K-12]]
[[Category: Singh, I]]
[[Category: Large Structures]]
[[Category: Ampc beta-lacatamase]]
[[Category: Singh I]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Inhibitor complex]]
[[Category: Phenolate]]

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