2zby
From Proteopedia
Crystal structure of vitamin D hydroxylase cytochrome P450 105A1 (R84A mutant)
Structural highlights
FunctionEvolutionary ConservationCheck, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedVitamin D 3 (VD 3), a prohormone in mammals, plays a crucial role in the maintenance of calcium and phosphorus concentrations in serum. Activation of VD 3 requires 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney by cytochrome P450 (CYP) enzymes. Bacterial CYP105A1 converts VD 3 into 1alpha,25-dihydroxyvitamin D 3 (1alpha,25(OH) 2D 3) in two independent reactions, despite its low sequence identity with mammalian enzymes (<21% identity). The present study determined the crystal structures of a highly active mutant (R84A) of CYP105A1 from Streptomyces griseolus in complex and not in complex with 1alpha,25(OH) 2D 3. The compound 1alpha,25(OH) 2D 3 is positioned 11 A from the iron atom along the I helix within the pocket. A similar binding mode is observed in the structure of the human CYP2R1-VD 3 complex, indicating a common substrate-binding mechanism for 25-hydroxylation. A comparison with the structure of wild-type CYP105A1 suggests that the loss of two hydrogen bonds in the R84A mutant increases the adaptability of the B' and F helices, creating a transient binding site. Further mutational analysis of the active site reveals that 25- and 1alpha-hydroxylations share residues that participate in these reactions. These results provide the structural basis for understanding the mechanism of the two-step hydroxylation that activates VD 3. Crystal Structure of CYP105A1 (P450SU-1) in Complex with 1alpha,25-Dihydroxyvitamin D3(,).,Sugimoto H, Shinkyo R, Hayashi K, Yoneda S, Yamada M, Kamakura M, Ikushiro S, Shiro Y, Sakaki T Biochemistry. 2008 Apr 1;47(13):4017-27. Epub 2008 Mar 4. PMID:18314962[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Large Structures | Streptomyces griseolus | Hayashi K | Ikushiro S | Kamakura M | Sakaki T | Shinkyo R | Shiro Y | Sugimoto H | Yamada M | Yoneda S