5vbu: Difference between revisions
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New page: '''Unreleased structure''' The entry 5vbu is ON HOLD Authors: Pallan, P.S., Egli, M. Description: Crystal Structure of Human Cytochrome P450 21A2 Hydroxyprogesterone Complex [[Category... |
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The entry | ==Crystal Structure of Human Cytochrome P450 21A2 Hydroxyprogesterone Complex== | ||
<StructureSection load='5vbu' size='340' side='right'caption='[[5vbu]], [[Resolution|resolution]] 3.31Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5vbu]] is a 3 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=5VBU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VBU 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]] 3.31Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QZ:(9BETA)-17-HYDROXYPREGN-4-ENE-3,20-DIONE'>3QZ</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=5vbu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vbu OCA], [https://pdbe.org/5vbu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vbu RCSB], [https://www.ebi.ac.uk/pdbsum/5vbu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vbu ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CP21A_HUMAN CP21A_HUMAN] Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form;Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CP21A_HUMAN CP21A_HUMAN] A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids (PubMed:10602386, PubMed:16984992, PubMed:22014889, PubMed:25855791, PubMed:27721825). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:25855791).<ref>PMID:10602386</ref> <ref>PMID:16984992</ref> <ref>PMID:22014889</ref> <ref>PMID:25855791</ref> <ref>PMID:27721825</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17alpha-OH-progesterone). We found that the 17alpha-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37-13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (>/= 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3-progesterone, indicating that C-H bond breaking is a rate-limiting step over a 104-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme. | |||
Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia.,Wang C, Pallan PS, Zhang W, Lei L, Yoshimoto FK, Waterman MR, Egli M, Guengerich FP J Biol Chem. 2017 Jun 30;292(26):10767-10778. doi: 10.1074/jbc.M117.792465. Epub , 2017 May 24. PMID:28539365<ref>PMID:28539365</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5vbu" style="background-color:#fffaf0;"></div> | ||
[[Category: Egli | |||
==See Also== | |||
*[[Cytochrome P450 hydroxylase 3D structures|Cytochrome P450 hydroxylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Egli M]] | |||
[[Category: Pallan PS]] | |||
