9f2q
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of Keap1 kelch domain in complex with a tetrahydroisoquinoline-based small molecule inhibitor at 1.2A resolution== | |
| + | <StructureSection load='9f2q' size='340' side='right'caption='[[9f2q]], [[Resolution|resolution]] 1.20Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9f2q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9F2Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9F2Q 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]] 1.2Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H9B:(2~{R})-2-[2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1~{H}-isoquinolin-7-yl]-2-[(9-oxidanylidenefluoren-4-yl)carbonylamino]ethanoic+acid'>A1H9B</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9f2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9f2q OCA], [https://pdbe.org/9f2q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9f2q RCSB], [https://www.ebi.ac.uk/pdbsum/9f2q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9f2q ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/KEAP1_MOUSE KEAP1_MOUSE] Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).<ref>PMID:9887101</ref> <ref>PMID:12682069</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inhibition of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as an attractive approach for treating oxidative stress-related diseases. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed by a conformational restriction strategy of our fluorenone-based compounds previously identified by fragment-based drug discovery. The design was guided by X-ray cocrystal structures, and the subsequent optimization process aimed at improving affinity, cellular activity, and metabolic stability. From the noncyclic compound 7 (K(i) = 2.9 muM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (57, K(i) = 13 nM), better metabolic stability, and enhanced cellular activity was obtained. In addition, the compounds showed selectivity for the Keap1 Kelch domain across a panel of 15 homologous proteins. We thereby demonstrate the utility of cyclic rigidification in the design of potent and more drug-like Keap1-Nrf2 inhibitors. | ||
| - | + | Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors.,Qin Y, Poulsen C, Narayanan D, Chan CB, Chen X, Montes BR, Tran KT, Mukminova E, Lin C, Gajhede M, Bullock AN, Olagnier D, Bach A J Med Chem. 2024 Oct 17. doi: 10.1021/acs.jmedchem.4c01221. PMID:39418396<ref>PMID:39418396</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9f2q" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mus musculus]] | ||
| + | [[Category: Bach A]] | ||
| + | [[Category: Gajhede M]] | ||
| + | [[Category: Narayanan D]] | ||
Current revision
Crystal structure of Keap1 kelch domain in complex with a tetrahydroisoquinoline-based small molecule inhibitor at 1.2A resolution
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