6p0p

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'''Unreleased structure'''
 
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The entry 6p0p is ON HOLD until Paper Publication
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==Human beta-tryptase co-crystal structure with 5-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-2-(3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-[1,1'-biphenyl]-3-yl)-2-hydroxy-2H-1,3,2-benzodioxaborol-2-uide==
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<StructureSection load='6p0p' size='340' side='right'caption='[[6p0p]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6p0p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P0P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P0P FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=Y35:(3-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}[1,1-biphenyl]-3-yl){4-[3-(aminomethyl)phenyl]piperidin-1-yl}[3,4-di(hydroxy-kappaO)phenyl]methanonato(2-)hydroxyborate(1-)'>Y35</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tryptase Tryptase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.59 3.4.21.59] </span></td></tr>
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<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=6p0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p0p OCA], [http://pdbe.org/6p0p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p0p RCSB], [http://www.ebi.ac.uk/pdbsum/6p0p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p0p ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/TRYB1_HUMAN TRYB1_HUMAN]] Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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beta-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.
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Authors:
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Novel, Self-Assembling Dimeric Inhibitors of Human beta Tryptase.,Giardina SF, Werner DS, Pingle M, Feinberg PB, Foreman KW, Bergstrom DE, Arnold LD, Barany F J Med Chem. 2020 Feb 27. doi: 10.1021/acs.jmedchem.9b01689. PMID:32057241<ref>PMID:32057241</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6p0p" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Tryptase]]
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[[Category: Arnold, L D]]
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[[Category: Barany, F]]
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[[Category: Bergstrom, D E]]
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[[Category: Feinberg, P B]]
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[[Category: Foreman, K W]]
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[[Category: Giardina, S F]]
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[[Category: Pingle, M R]]
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[[Category: Werner, D S]]
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[[Category: Bivalent inhibitor]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Protease inhibitor]]

Revision as of 10:11, 27 March 2020

Human beta-tryptase co-crystal structure with 5-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-2-(3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-[1,1'-biphenyl]-3-yl)-2-hydroxy-2H-1,3,2-benzodioxaborol-2-uide

PDB ID 6p0p

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