6z6a: Difference between revisions
New page: '''Unreleased structure''' The entry 6z6a is ON HOLD Authors: Johansson, P. Description: Keap1 macrocycle complex Category: Unreleased Structures Category: Johansson, P |
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The | ==Keap1 macrocycle complex== | ||
<StructureSection load='6z6a' size='340' side='right'caption='[[6z6a]], [[Resolution|resolution]] 2.37Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6z6a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z6A 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]] 2.37Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Q9E:(5S,8R)-8-[[(2S)-1-ethanoylpyrrolidin-2-yl]carbonylamino]-N,N-dimethyl-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carboxamide'>Q9E</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=6z6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z6a OCA], [https://pdbe.org/6z6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z6a RCSB], [https://www.ebi.ac.uk/pdbsum/6z6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z6a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keap1 and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections. | |||
Mining Natural Products for Macrocycles to Drug Difficult Targets.,Begnini F, Poongavanam V, Over B, Castaldo M, Geschwindner S, Johansson P, Tyagi M, Tyrchan C, Wissler L, Sjo P, Schiesser S, Kihlberg J J Med Chem. 2020 Dec 18. doi: 10.1021/acs.jmedchem.0c01569. PMID:33337880<ref>PMID:33337880</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Johansson | <div class="pdbe-citations 6z6a" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Johansson P]] | |||
Latest revision as of 16:42, 24 January 2024
Keap1 macrocycle complexKeap1 macrocycle complex
Structural highlights
FunctionPublication Abstract from PubMedLead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keap1 and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections. Mining Natural Products for Macrocycles to Drug Difficult Targets.,Begnini F, Poongavanam V, Over B, Castaldo M, Geschwindner S, Johansson P, Tyagi M, Tyrchan C, Wissler L, Sjo P, Schiesser S, Kihlberg J J Med Chem. 2020 Dec 18. doi: 10.1021/acs.jmedchem.0c01569. PMID:33337880[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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