6uqd
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Co-complex of S. pyogenes 10782 streptopain bound with a SuFEx-based optimized small molecule inhibitor== | ==Co-complex of S. pyogenes 10782 streptopain bound with a SuFEx-based optimized small molecule inhibitor== | ||
| - | <StructureSection load='6uqd' size='340' side='right'caption='[[6uqd]]' scene=''> | + | <StructureSection load='6uqd' size='340' side='right'caption='[[6uqd]], [[Resolution|resolution]] 2.02Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UQD OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6uqd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptococcus_pyogenes Streptococcus pyogenes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UQD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UQD FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.02Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QF4:benzyl+[(1S)-2-(3-{[(4-carbamoylpiperidin-1-yl)(fluoro)oxo-lambda~6~-sulfanylidene]amino}phenyl)-1-cyanoethyl]carbamate'>QF4</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=6uqd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uqd OCA], [https://pdbe.org/6uqd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uqd RCSB], [https://www.ebi.ac.uk/pdbsum/6uqd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uqd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/SPEB_STRPY SPEB_STRPY] Important streptococcal virulence factor which cleaves human fibronectin and degrades vitronectin. Also cleaves human IL1B precursor to form biologically active IL1B. Can induce apoptosis in human monocytes and epithelial cells in vitro, and reduces phagocytic activity in monocytic cells. Thus, may play a role in bacterial colonization, invasion, and inhibition of wound healing.<ref>PMID:9864206</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible sulfur(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)carbamate (Ki = 8 muM) against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN horizontal lineS(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products were directly screened to yield drug-like inhibitors with 480-fold higher potency (Ki = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates. | ||
| + | |||
| + | Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry.,Kitamura S, Zheng Q, Woehl JL, Solania A, Chen E, Dillon N, Hull MV, Kotaniguchi M, Cappiello JR, Kitamura S, Nizet V, Sharpless KB, Wolan DW J Am Chem Soc. 2020 Jun 24;142(25):10899-10904. doi: 10.1021/jacs.9b13652. Epub, 2020 Jun 10. PMID:32479075<ref>PMID:32479075</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6uqd" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Streptococcus pyogenes]] | ||
[[Category: Kitamura S]] | [[Category: Kitamura S]] | ||
[[Category: Woehl JL]] | [[Category: Woehl JL]] | ||
[[Category: Wolan DW]] | [[Category: Wolan DW]] | ||
Current revision
Co-complex of S. pyogenes 10782 streptopain bound with a SuFEx-based optimized small molecule inhibitor
| |||||||||||
