4jlt: Difference between revisions
New page: '''Unreleased structure''' The entry 4jlt is ON HOLD Authors: M.B.SHAH, J.PASCUAL, C.D.STOUT, J.R.HALPERT Description: CRYSTAL STRUCTURE OF P450 2B4(H226Y) IN COMPLEX WITH PAROXETINE |
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The | ==Crystal structure of P450 2B4(H226Y) in complex with paroxetine== | ||
<StructureSection load='4jlt' size='340' side='right'caption='[[4jlt]], [[Resolution|resolution]] 2.14Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4jlt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JLT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JLT 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]] 2.14Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8PR:PAROXETINE'>8PR</scene>, <scene name='pdbligand=CM5:5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE'>CM5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4jlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jlt OCA], [https://pdbe.org/4jlt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jlt RCSB], [https://www.ebi.ac.uk/pdbsum/4jlt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jlt ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CP2B4_RABIT CP2B4_RABIT] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it has a unique preference for the 5,6-olefin. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
An X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 A resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active-site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands. | |||
A Structural Snapshot of CYP2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States.,Shah MB, Kufareva I, Pascual J, Zhang Q, Stout CD, Halpert JR J Pharmacol Exp Ther. 2013 Jul;346(1):113-20. doi: 10.1124/jpet.113.204776. Epub , 2013 Apr 30. PMID:23633618<ref>PMID:23633618</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4jlt" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Oryctolagus cuniculus]] | |||
[[Category: Halpert JR]] | |||
[[Category: Pascual J]] | |||
[[Category: Shah MB]] | |||
[[Category: Stout CD]] | |||
Latest revision as of 18:45, 20 September 2023
Crystal structure of P450 2B4(H226Y) in complex with paroxetineCrystal structure of P450 2B4(H226Y) in complex with paroxetine
Structural highlights
FunctionCP2B4_RABIT Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it has a unique preference for the 5,6-olefin. Publication Abstract from PubMedAn X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 A resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active-site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands. A Structural Snapshot of CYP2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States.,Shah MB, Kufareva I, Pascual J, Zhang Q, Stout CD, Halpert JR J Pharmacol Exp Ther. 2013 Jul;346(1):113-20. doi: 10.1124/jpet.113.204776. Epub , 2013 Apr 30. PMID:23633618[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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