2ZBX

Crystal structure of vitamin D hydroxylase cytochrome P450 105A1 (wild type) with imidazole bound

Summary for 2ZBX

• Entry DOI: 10.2210/pdb2zbx/pdb
• Related: 2ZBY 2ZBZ
• Descriptor: Cytochrome P450-SU1, PROTOPORPHYRIN IX CONTAINING FE, IMIDAZOLE, ... (4 entities in total)
• Functional Keywords: p450, beta prism, heme, iron, metal-binding, monooxygenase, oxidoreductase
• Biological source: Streptomyces griseolus
• Total number of polymer chains: 1
• Total formula weight: 45763.43

Authors

Sugimoto, H.,Shinkyo, R.,Hayashi, K.,Yoneda, S.,Yamada, M.,Kamakura, M.,Ikushiro, S.,Shiro, Y.,Sakaki, T. (deposition date: 2007-10-30, release date: 2008-04-08, Last modification date: 2024-04-03)

Primary citation

Sugimoto, H.,Shinkyo, R.,Hayashi, K.,Yoneda, S.,Yamada, M.,Kamakura, M.,Ikushiro, S.,Shiro, Y.,Sakaki, T.
Crystal Structure of CYP105A1 (P450SU-1) in Complex with 1alpha,25-Dihydroxyvitamin D3
Biochemistry, 47:4017-4027, 2008

PubMed Abstract: Vitamin 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.

PubMed: 18314962
DOI: 10.1021/bi7023767

Experimental method

X-RAY DIFFRACTION (1.5 Å)