View source for 6dag


==Human CYP3A4 bound to an inhibitor==
<StructureSection load='6dag' size='340' side='right'caption='[[6dag]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dag]] 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=6DAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DAG 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]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G0Y:~{tert}-butyl+~{N}-[(2~{R})-1-[(2~{S})-1-oxidanylidene-3-phenyl-1-(2-pyridin-3-ylethylamino)propan-2-yl]sulfanyl-3-phenyl-propan-2-yl]carbamate'>G0Y</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=6dag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dag OCA], [https://pdbe.org/6dag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dag RCSB], [https://www.ebi.ac.uk/pdbsum/6dag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dag ProSAT]</span></td></tr>
</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> 
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== 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<ref>PMID:30912932</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6dag" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sevrioukova IF]]