View source for 8ijv


==Cryo-EM structure of the gastric proton pump with bound DQ-02==
<StructureSection load='8ijv' size='340' side='right'caption='[[8ijv]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ijv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8IJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IJV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BFD:ASPARTATE+BERYLLIUM+TRIFLUORIDE'>BFD</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</scene>, <scene name='pdbligand=PWI:4-[[5-chloranyl-2-(4-chlorophenyl)phenyl]methoxy]-~{N}-methyl-but-2-yn-1-amine'>PWI</scene></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=8ijv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ijv OCA], [https://pdbe.org/8ijv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ijv RCSB], [https://www.ebi.ac.uk/pdbsum/8ijv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ijv ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 A resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a K(i) value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 A resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.

Deep learning driven de novo drug design based on gastric proton pump structures.,Abe K, Ozako M, Inukai M, Matsuyuki Y, Kitayama S, Kanai C, Nagai C, Gopalasingam CC, Gerle C, Shigematsu H, Umekubo N, Yokoshima S, Yoshimori A Commun Biol. 2023 Sep 19;6(1):956. doi: 10.1038/s42003-023-05334-8. PMID:37726448<ref>PMID:37726448</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ijv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Sus scrofa]]
[[Category: Abe K]]
[[Category: Yokoshima S]]
[[Category: Yoshimori A]]