View source for 3qft


==Crystal Structure of NADPH-Cytochrome P450 Reductase (FAD/NADPH domain and R457H Mutant)==
<StructureSection load='3qft' size='340' side='right' caption='[[3qft]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3qft]] 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=3QFT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QFT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qe2|3qe2]], [[3qfc|3qfc]], [[3qfr|3qfr]], [[3qfs|3qfs]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POR, CYPOR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NADPH--hemoprotein_reductase NADPH--hemoprotein reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.6.2.4 1.6.2.4] </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=3qft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qft OCA], [http://pdbe.org/3qft PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qft RCSB], [http://www.ebi.ac.uk/pdbsum/3qft PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qft ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/NCPR_HUMAN NCPR_HUMAN]] Defects in POR are the cause of Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1) [MIM:[http://omim.org/entry/201750 201750]]. A disease characterized by the association of Antley-Bixler syndrome with steroidogenesis defects and abnormal genitalia. Antley-Bixler syndrome is characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures.<ref>PMID:15264278</ref> <ref>PMID:15483095</ref> <ref>PMID:14758361</ref>   Defects in POR are the cause of disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency (DISPORD) [MIM:[http://omim.org/entry/613571 613571]]. A disorder resulting in a rare variant of congenital adrenal hyperplasia, with apparent combined P450C17 and P450C21 deficiency and accumulation of steroid metabolites. Affected girls are born with ambiguous genitalia, but their circulating androgens are low and virilization does not progress. Conversely, affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, in some cases resembling the pattern seen in patients with Antley-Bixler syndrome.<ref>PMID:14758361</ref> <ref>PMID:15220035</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/NCPR_HUMAN NCPR_HUMAN]] This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
NADPH-cytochrome P450 oxidoreductase (CYPOR) is essential for electron donation to microsomal cytochrome P450-mediated monooxygenation in such diverse physiological processes as drug metabolism (approximately 85-90% of therapeutic drugs), steroid biosynthesis, and bioactive metabolite production (vitamin D and retinoic acid metabolites). Expressed by a single gene, CYPOR's role with these multiple redox partners renders it a model for understanding protein-protein interactions at the structural level. Polymorphisms in human CYPOR have been shown to lead to defects in bone development and steroidogenesis, resulting in sexual dimorphisms, the severity of which differs significantly depending on the degree of CYPOR impairment. The atomic structure of human CYPOR is presented, with structures of two naturally occurring missense mutations, V492E and R457H. The overall structures of these CYPOR variants are similar to wild type. However, in both variants, local disruption of H bonding and salt bridging, involving the FAD pyrophosphate moiety, leads to weaker FAD binding, unstable protein, and loss of catalytic activity, which can be rescued by cofactor addition. The modes of polypeptide unfolding in these two variants differ significantly, as revealed by limited trypsin digestion: V492E is less stable but unfolds locally and gradually, whereas R457H is more stable but unfolds globally. FAD addition to either variant prevents trypsin digestion, supporting the role of the cofactor in conferring stability to CYPOR structure. Thus, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy in utero, if predicted prenatally, or rescued postnatally in less severe cases.

Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency.,Xia C, Panda SP, Marohnic CC, Martasek P, Masters BS, Kim JJ Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13486-91. Epub 2011 Aug 1. PMID:21808038<ref>PMID:21808038</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3qft" style="background-color:#fffaf0;"></div>

==See Also==
*[[NADPH-Cytochrome P450 Reductase|NADPH-Cytochrome P450 Reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: NADPH--hemoprotein reductase]]
[[Category: Kim, J J.P]]
[[Category: Marohnic, C]]
[[Category: Masters, B S]]
[[Category: Panda, S P]]
[[Category: Xia, C]]
[[Category: Antley-bixler syndrome]]
[[Category: Fad]]
[[Category: Flavoprotein]]
[[Category: Nadph]]
[[Category: Nadph-cytochrome p450 reductase]]
[[Category: Oxidoreductase]]