View source for 7e7f


==Human CYP11B1 mutant in complex with metyrapone==
<StructureSection load='7e7f' size='340' side='right'caption='[[7e7f]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E7F 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]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CHD:CHOLIC+ACID'>CHD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MYT:METYRAPONE'>MYT</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=7e7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e7f OCA], [https://pdbe.org/7e7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e7f RCSB], [https://www.ebi.ac.uk/pdbsum/7e7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e7f ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human cytochromes P45011beta (CYP11B1) and P450aldo (CYP11B2) are monooxygenases that synthesize cortisol through steroid 11beta-hydroxylation and aldosterone through a three-step process comprising 11beta-hydroxylation and two 18-hydroxylations, respectively. CYP11B1 also catalyzes 18-monohydroxylation and 11beta,18-dihydroxylation. To study the molecular basis of such catalytic divergence of the two enzymes, we examined a CYP11B1 mutant (Mt-CYP11B1) with amino acid replacements on the distal surface by determining the catalytic activities and crystal structure in the metyrapone-bound form at 1.4-A resolution. Mt-CY11B1 retained both 11beta-hydroxylase and 18-hydroxylase activities of the wild type (Wt-CYP11B1) but lacked 11beta,18-dihydroxylase activity. Comparisons of the crystal structure of Mt-CYP11B1 to those of Wt-CYP11B1 and CYP11B2 that were already reported show that the mutation reduced the innermost space putatively surrounding the C3 side of substrate 11-deoxycorticosterone (DOC) bound to Wt-CYP11B1, while the corresponding space in CYP11B2 is enlarged markedly and accessible to bulk water through a channel. Molecular dynamics simulations of their DOC-bound forms supported the above findings and revealed that the enlarged space of CYP11B2 had a hydrogen bonding network involving water molecules that position DOC. Thus, upon positioning 11beta-hydroxysteroid for 18-hydroxylation in their substrate-binding sites, steric hindrance could occur more strongly in Mt-CYP11B1 than in Wt-CYP11B1 but less in CYP11B2. Our investigation employing Mt-CYP11B1 sheds light on the divergence in structure and function between CYP11B1 and CYP11B2 and suggests that CYP11B1 with spatially-restricted substrate-binding site serves as 11beta-hydroxylase, while CYP11B2 with spatially-extended substrate-binding site successively processes additional 18-hydroxylations to produce aldosterone.

Spatially restricted substrate-binding site of cortisol-synthesizing CYP11B1 limits multiple hydroxylations and hinders aldosterone synthesis.,Mukai K, Sugimoto H, Kamiya K, Suzuki R, Matsuura T, Hishiki T, Shimada H, Shiro Y, Suematsu M, Kagawa N Curr Res Struct Biol. 2021 Aug 26;3:192-205. doi: 10.1016/j.crstbi.2021.08.001., eCollection 2021. PMID:34485929<ref>PMID:34485929</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7e7f" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Hishiki T]]
[[Category: Kagawa N]]
[[Category: Matsuura T]]
[[Category: Mukai K]]
[[Category: Reiko S]]
[[Category: Sugimoto H]]