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| - | [[Image:1b1c.gif|left|200px]]<br /> | |
| - | <applet load="1b1c" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1b1c, resolution 1.93Å" /> | |
| - | '''CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE AT 1.93A RESOLUTION'''<br /> | |
| | | | |
| - | ==Overview== | + | ==CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE AT 1.93A RESOLUTION== |
| - | The crystal structure of the FMN-binding domain of human NADPH-cytochrome, P450 reductase (P450R-FMN), a key component in the cytochrome P450, monooxygenase system, has been determined to 1.93 A resolution and shown, to be very similar both to the global fold in solution (Barsukov I et al., 1997, J Biomol NMR 10:63-75) and to the corresponding domain in the 2.6 A, crystal structure of intact rat P450R (Wang M et al., 1997, Proc Nat Acad, Sci USA 94:8411-8416). The crystal structure of P450R-FMN reported here, confirms the overall similarity of its alpha-beta-alpha architecture to, that of the bacterial flavodoxins, but reveals differences in the, position, number, and length of the helices relative to the central, beta-sheet. The marked similarity between P450R-FMN and flavodoxins in the, interactions between the FMN and the protein, indicate a striking, evolutionary conservation of the FMN binding site. The P450R-FMN molecule, has an unusual surface charge distribution, leading to a very strong, dipole, which may be involved in docking cytochrome P450 into place for, electron transfer near the FMN. Several acidic residues near the FMN are, identified by mutagenesis experiments to be important for electron, transfer to P4502D6 and to cytochrome c, a clear indication of the part of, the molecular surface that is likely to be involved in substrate binding., Somewhat different parts are found to be involved in binding cytochrome, P450 and cytochrome c. | + | <StructureSection load='1b1c' size='340' side='right'caption='[[1b1c]], [[Resolution|resolution]] 1.93Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1b1c]] is a 1 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=1B1C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1B1C 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]] 1.93Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</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=1b1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1b1c OCA], [https://pdbe.org/1b1c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1b1c RCSB], [https://www.ebi.ac.uk/pdbsum/1b1c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1b1c ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://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:[https://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:[https://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 == |
| | + | [https://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. |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/b1/1b1c_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1b1c ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The crystal structure of the FMN-binding domain of human NADPH-cytochrome P450 reductase (P450R-FMN), a key component in the cytochrome P450 monooxygenase system, has been determined to 1.93 A resolution and shown to be very similar both to the global fold in solution (Barsukov I et al., 1997, J Biomol NMR 10:63-75) and to the corresponding domain in the 2.6 A crystal structure of intact rat P450R (Wang M et al., 1997, Proc Nat Acad Sci USA 94:8411-8416). The crystal structure of P450R-FMN reported here confirms the overall similarity of its alpha-beta-alpha architecture to that of the bacterial flavodoxins, but reveals differences in the position, number, and length of the helices relative to the central beta-sheet. The marked similarity between P450R-FMN and flavodoxins in the interactions between the FMN and the protein, indicate a striking evolutionary conservation of the FMN binding site. The P450R-FMN molecule has an unusual surface charge distribution, leading to a very strong dipole, which may be involved in docking cytochrome P450 into place for electron transfer near the FMN. Several acidic residues near the FMN are identified by mutagenesis experiments to be important for electron transfer to P4502D6 and to cytochrome c, a clear indication of the part of the molecular surface that is likely to be involved in substrate binding. Somewhat different parts are found to be involved in binding cytochrome P450 and cytochrome c. |
| | | | |
| - | ==Disease==
| + | Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 A resolution.,Zhao Q, Modi S, Smith G, Paine M, McDonagh PD, Wolf CR, Tew D, Lian LY, Roberts GC, Driessen HP Protein Sci. 1999 Feb;8(2):298-306. PMID:10048323<ref>PMID:10048323</ref> |
| - | Known diseases associated with this structure: Adrenal hyperplasia, congenital, due to combined P450C17 and P450C21 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124015 124015]], Antley-Bixler syndrome-like with disordered steroidogenesis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124015 124015]], Disordered steroidogenesis, isolated OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124015 124015]], POR deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124015 124015]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1B1C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA and FMN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1B1C OCA].
| + | </div> |
| | + | <div class="pdbe-citations 1b1c" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 A resolution., Zhao Q, Modi S, Smith G, Paine M, McDonagh PD, Wolf CR, Tew D, Lian LY, Roberts GC, Driessen HP, Protein Sci. 1999 Feb;8(2):298-306. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10048323 10048323]
| + | *[[NADPH-Cytochrome P450 Reductase|NADPH-Cytochrome P450 Reductase]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: NADPH--hemoprotein reductase]] | + | [[Category: Large Structures]] |
| - | [[Category: Single protein]]
| + | [[Category: Driessen HPC]] |
| - | [[Category: Driessen, H.P.C.]] | + | [[Category: Lian L-Y]] |
| - | [[Category: Lian, L.Y.]] | + | [[Category: Mcdonagh PD]] |
| - | [[Category: Mcdonagh, P.D.]] | + | [[Category: Modi S]] |
| - | [[Category: Modi, S.]] | + | [[Category: Paine M]] |
| - | [[Category: Paine, M.]] | + | [[Category: Roberts GCK]] |
| - | [[Category: Roberts, G.C.K.]] | + | [[Category: Smith G]] |
| - | [[Category: Smith, G.]] | + | [[Category: Tew D]] |
| - | [[Category: Tew, D.]] | + | [[Category: Wolf CR]] |
| - | [[Category: Wolf, C.R.]] | + | [[Category: Zhao Q]] |
| - | [[Category: Zhao, Q.]] | + | |
| - | [[Category: CA]]
| + | |
| - | [[Category: FMN]]
| + | |
| - | [[Category: cytochrome p450 reductase]]
| + | |
| - | [[Category: flavoprotein]]
| + | |
| - | [[Category: fmn]]
| + | |
| - | [[Category: fmn-binding domain]]
| + | |
| - | [[Category: p450 reductase]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:04:37 2007''
| + | |
| Structural highlights
Disease
NCPR_HUMAN Defects in POR are the cause of Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1) [MIM: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.[1] [2] [3] Defects in POR are the cause of disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency (DISPORD) [MIM: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.[4] [5]
Function
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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The crystal structure of the FMN-binding domain of human NADPH-cytochrome P450 reductase (P450R-FMN), a key component in the cytochrome P450 monooxygenase system, has been determined to 1.93 A resolution and shown to be very similar both to the global fold in solution (Barsukov I et al., 1997, J Biomol NMR 10:63-75) and to the corresponding domain in the 2.6 A crystal structure of intact rat P450R (Wang M et al., 1997, Proc Nat Acad Sci USA 94:8411-8416). The crystal structure of P450R-FMN reported here confirms the overall similarity of its alpha-beta-alpha architecture to that of the bacterial flavodoxins, but reveals differences in the position, number, and length of the helices relative to the central beta-sheet. The marked similarity between P450R-FMN and flavodoxins in the interactions between the FMN and the protein, indicate a striking evolutionary conservation of the FMN binding site. The P450R-FMN molecule has an unusual surface charge distribution, leading to a very strong dipole, which may be involved in docking cytochrome P450 into place for electron transfer near the FMN. Several acidic residues near the FMN are identified by mutagenesis experiments to be important for electron transfer to P4502D6 and to cytochrome c, a clear indication of the part of the molecular surface that is likely to be involved in substrate binding. Somewhat different parts are found to be involved in binding cytochrome P450 and cytochrome c.
Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 A resolution.,Zhao Q, Modi S, Smith G, Paine M, McDonagh PD, Wolf CR, Tew D, Lian LY, Roberts GC, Driessen HP Protein Sci. 1999 Feb;8(2):298-306. PMID:10048323[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Adachi M, Tachibana K, Asakura Y, Yamamoto T, Hanaki K, Oka A. Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. Am J Med Genet A. 2004 Aug 1;128A(4):333-9. PMID:15264278 doi:10.1002/ajmg.a.30169
- ↑ Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, Okuyama T, Nakai H, Soneda S, Tachibana K, Matsuo N, Sato S, Homma K, Nishimura G, Hasegawa T, Ogata T. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. 2005 Jan;90(1):414-26. Epub 2004 Oct 13. PMID:15483095 doi:jc.2004-0810
- ↑ Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004 Mar;36(3):228-30. Epub 2004 Feb 1. PMID:14758361 doi:10.1038/ng1300
- ↑ Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004 Mar;36(3):228-30. Epub 2004 Feb 1. PMID:14758361 doi:10.1038/ng1300
- ↑ Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM, Stewart PM, Shackleton CH. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. 2004 Jun 26;363(9427):2128-35. PMID:15220035 doi:10.1016/S0140-6736(04)16503-3
- ↑ Zhao Q, Modi S, Smith G, Paine M, McDonagh PD, Wolf CR, Tew D, Lian LY, Roberts GC, Driessen HP. Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 A resolution. Protein Sci. 1999 Feb;8(2):298-306. PMID:10048323
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