This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
7n3m
From Proteopedia
(Difference between revisions)
| (One intermediate revision not shown.) | |||
| Line 1: | Line 1: | ||
==Co-complex CYP46A1 with 0431 (compound 17)== | ==Co-complex CYP46A1 with 0431 (compound 17)== | ||
| - | <StructureSection load='7n3m' size='340' side='right'caption='[[7n3m]]' scene=''> | + | <StructureSection load='7n3m' size='340' side='right'caption='[[7n3m]], [[Resolution|resolution]] 1.70Å' 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=7N3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N3M FirstGlance]. <br> | + | <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='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> | + | </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> | </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> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7n3m" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lane W]] | [[Category: Lane W]] | ||
[[Category: Yano J]] | [[Category: Yano J]] | ||
Current revision
Co-complex CYP46A1 with 0431 (compound 17)
| |||||||||||
