|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6da5' size='340' side='right'caption='[[6da5]], [[Resolution|resolution]] 2.25Å' scene=''> | | <StructureSection load='6da5' size='340' side='right'caption='[[6da5]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6da5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DA5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6da5]] 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=6DA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DA5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G1J:tert-butyl+[(2R)-1-{[(2S)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G1J</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></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]] 2.25Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G1J:tert-butyl+[(2R)-1-{[(2S)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G1J</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6da5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da5 OCA], [http://pdbe.org/6da5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6da5 RCSB], [http://www.ebi.ac.uk/pdbsum/6da5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6da5 ProSAT]</span></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=6da5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da5 OCA], [https://pdbe.org/6da5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6da5 RCSB], [https://www.ebi.ac.uk/pdbsum/6da5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6da5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 26: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sevrioukova, I F]] | + | [[Category: Sevrioukova IF]] |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| 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 PubMed
In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogs differing in the side-group stereochemistry, backbone atomic composition, and head-group spacing. All analogs had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and tail groups, respectively, phenyl side-groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/R, R/S, R/R and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant (Ks), inhibitory potency (IC50), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogs, and strongly disfavors the N-containing backbone. Ks and IC50 for the pyridyl-ethyl R/R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 microM versus 0.02 and 0.13 microM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis we conclude that, for this series of analogs, the ligand-mediated interactions near the heme are dominant and define the binding mode, and that fine-tuning of these interactions, as well as the backbone spacing could further improve the affinity and inhibitory strength.
Structure-activity relationships of rationally designed ritonavir analogs: Impact of side-group stereochemistry, head-group spacing, and backbone composition on the interaction with CYP3A4.,Samuels ER, Sevrioukova I Biochemistry. 2019 Mar 26. doi: 10.1021/acs.biochem.9b00156. PMID:30912932[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Miyazawa M, Shindo M, Shimada T. Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metab Dispos. 2001 Feb;29(2):200-5. PMID:11159812
- ↑ Samuels ER, Sevrioukova I. Structure-activity relationships of rationally designed ritonavir analogs: Impact of side-group stereochemistry, head-group spacing, and backbone composition on the interaction with CYP3A4. Biochemistry. 2019 Mar 26. doi: 10.1021/acs.biochem.9b00156. PMID:30912932 doi:http://dx.doi.org/10.1021/acs.biochem.9b00156
|
