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.
7ufb
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==CYP3A4 bound to an inhibitor== | ==CYP3A4 bound to an inhibitor== | ||
| - | <StructureSection load='7ufb' size='340' side='right'caption='[[7ufb]]' scene=''> | + | <StructureSection load='7ufb' size='340' side='right'caption='[[7ufb]], [[Resolution|resolution]] 2.25Å' 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=7UFB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UFB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ufb]] 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=7UFB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UFB 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=7ufb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ufb OCA], [https://pdbe.org/7ufb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ufb RCSB], [https://www.ebi.ac.uk/pdbsum/7ufb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ufb ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NJ0:(2R)-3-phenyl-2-({(2S)-3-phenyl-2-[2-(pyridin-3-yl)acetamido]propyl}sulfanyl)-N-[(pyridin-3-yl)methyl]propanamide'>NJ0</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=7ufb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ufb OCA], [https://pdbe.org/7ufb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ufb RCSB], [https://www.ebi.ac.uk/pdbsum/7ufb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ufb ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure-activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers' length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization. | ||
| + | |||
| + | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.,Samuels ER, Sevrioukova IF Int J Mol Sci. 2022 Jun 30;23(13). pii: ijms23137291. doi: 10.3390/ijms23137291. PMID:35806297<ref>PMID:35806297</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ufb" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Sevrioukova I]] | [[Category: Sevrioukova I]] | ||
Revision as of 04:16, 8 September 2022
CYP3A4 bound to an inhibitor
| |||||||||||
