5t6q: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of cytochrome P450 4B1 (CYP4B1) complexed with octane: An n-Alkane and fatty acid omega-hydroxylase with a covalently bound heme== | |||
<StructureSection load='5t6q' size='340' side='right' caption='[[5t6q]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5t6q]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T6Q 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=OCT:N-OCTANE'>OCT</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </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=5t6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6q OCA], [http://pdbe.org/5t6q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t6q RCSB], [http://www.ebi.ac.uk/pdbsum/5t6q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6q ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/CP4B1_RABIT CP4B1_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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
P450 family 4 fatty acid omega-hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for omega-hydroxylation. The structure indicated that octane is bound in a narrow active site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for omega-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized E310 contributes to substrate positioning. The preference for omega-hydroxylation was decreased in a E310A mutant having a shorter side-chain, but overall rates of metabolism were retained. E310D and E310Q substitutions having longer side-chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane omega-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for omega-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for omega-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of un-activated primary C-H bonds. | |||
The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monoxygenase Complexed with Octane Discloses Several Structural Adaptations for omega-Hydroxylation.,Hsu MH, Baer BR, Rettie AE, Johnson EF J Biol Chem. 2017 Feb 6. pii: jbc.M117.775494. doi: 10.1074/jbc.M117.775494. PMID:28167536<ref>PMID:28167536</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5t6q" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Unspecific monooxygenase]] | |||
[[Category: Hsu, M]] | [[Category: Hsu, M]] | ||
[[Category: Johnson, E | [[Category: Johnson, E F]] | ||
[[Category: Cyp4b1]] | |||
[[Category: Cytochrome p450]] | |||
[[Category: Fatty acid omega-hydroxylase]] | |||
[[Category: Octane]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 11:26, 9 March 2017
Structure of cytochrome P450 4B1 (CYP4B1) complexed with octane: An n-Alkane and fatty acid omega-hydroxylase with a covalently bound hemeStructure of cytochrome P450 4B1 (CYP4B1) complexed with octane: An n-Alkane and fatty acid omega-hydroxylase with a covalently bound heme
Structural highlights
Function[CP4B1_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. Publication Abstract from PubMedP450 family 4 fatty acid omega-hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for omega-hydroxylation. The structure indicated that octane is bound in a narrow active site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for omega-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized E310 contributes to substrate positioning. The preference for omega-hydroxylation was decreased in a E310A mutant having a shorter side-chain, but overall rates of metabolism were retained. E310D and E310Q substitutions having longer side-chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane omega-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for omega-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for omega-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of un-activated primary C-H bonds. The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monoxygenase Complexed with Octane Discloses Several Structural Adaptations for omega-Hydroxylation.,Hsu MH, Baer BR, Rettie AE, Johnson EF J Biol Chem. 2017 Feb 6. pii: jbc.M117.775494. doi: 10.1074/jbc.M117.775494. PMID:28167536[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||