7uf9: Difference between revisions
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==CYP3A4 bound to an inhibitor== | ==CYP3A4 bound to an inhibitor== | ||
<StructureSection load='7uf9' size='340' side='right'caption='[[7uf9]]' scene=''> | <StructureSection load='7uf9' size='340' side='right'caption='[[7uf9]], [[Resolution|resolution]] 2.45Å' 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=7UF9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UF9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7uf9]] 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=7UF9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UF9 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=7uf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uf9 OCA], [https://pdbe.org/7uf9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uf9 RCSB], [https://www.ebi.ac.uk/pdbsum/7uf9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uf9 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=NH0:tert-butyl+[(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[2-(pyridin-4-yl)ethyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>NH0</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=7uf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uf9 OCA], [https://pdbe.org/7uf9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uf9 RCSB], [https://www.ebi.ac.uk/pdbsum/7uf9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uf9 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 7uf9" 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 07:16, 8 September 2022
CYP3A4 bound to an inhibitorCYP3A4 bound to an inhibitor
Structural highlights
Function[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.[1] Publication Abstract from PubMedControlled 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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