6unl
From Proteopedia
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<StructureSection load='6unl' size='340' side='right'caption='[[6unl]], [[Resolution|resolution]] 2.55Å' scene=''> | <StructureSection load='6unl' size='340' side='right'caption='[[6unl]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6unl]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UNL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UNL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6unl]] 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=6UNL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UNL FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=QDJ:tert-butyl+[(2R)-1-(naphthalen-1-yl)-3-{[(2S)-3-(naphthalen-1-yl)-1-oxo-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate'>QDJ</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=QDJ:tert-butyl+[(2R)-1-(naphthalen-1-yl)-3-{[(2S)-3-(naphthalen-1-yl)-1-oxo-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate'>QDJ</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6une|6une]], [[6ung|6ung]], [[6unh|6unh]], [[6uni|6uni]], [[6unj|6unj]], [[6unk|6unk]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6une|6une]], [[6ung|6ung]], [[6unh|6unh]], [[6uni|6uni]], [[6unj|6unj]], [[6unk|6unk]]</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='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=6unl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6unl OCA], [http://pdbe.org/6unl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6unl RCSB], [http://www.ebi.ac.uk/pdbsum/6unl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6unl ProSAT]</span></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=6unl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6unl OCA], [http://pdbe.org/6unl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6unl RCSB], [http://www.ebi.ac.uk/pdbsum/6unl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6unl 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> | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055-0.085 muM vs. 0.130 muM, respectively). | ||
| + | |||
| + | An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.,Samuels ER, Sevrioukova IF Bioorg Med Chem. 2020 Mar 15;28(6):115349. doi: 10.1016/j.bmc.2020.115349. Epub, 2020 Jan 31. PMID:32044230<ref>PMID:32044230</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6unl" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Sevrioukova, I]] | [[Category: Sevrioukova, I]] | ||
Revision as of 10:34, 26 February 2020
CYP3A4 bound to an inhibitor
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