7n3m
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 7n3m is ON HOLD Authors: Lane, W., Yano, J. Description: Co-complex CYP46A1 with TR06180431 (compound 17) Category: Unreleased Structures [[Cat...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Co-complex CYP46A1 with 0431 (compound 17)== | |
| + | <StructureSection load='7n3m' size='340' side='right'caption='[[7n3m]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7n3m]] is a 1 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=7N3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N3M 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]] 1.698Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=05D:N,N-dimethyl-1-[4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl]piperidine-4-carboxamide'>05D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=7n3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n3m OCA], [https://pdbe.org/7n3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n3m RCSB], [https://www.ebi.ac.uk/pdbsum/7n3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n3m ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CP46A_HUMAN CP46A_HUMAN] Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H. | ||
| - | + | Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.,Kajita Y, Ikeda S, Yoshikawa M, Fukuda H, Watanabe E, Yano J, Lane W, Miyamoto M, Ishii T, Nishi T, Koike T J Med Chem. 2022 Feb 24;65(4):3343-3358. doi: 10.1021/acs.jmedchem.1c01898. Epub , 2022 Feb 15. PMID:35166541<ref>PMID:35166541</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 7n3m" style="background-color:#fffaf0;"></div> |
| - | [[Category: Lane | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lane W]] | ||
| + | [[Category: Yano J]] | ||
Current revision
Co-complex CYP46A1 with 0431 (compound 17)
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