Introduction
Rickets is a disease caused by a vitamin D deficiency. Vitamin D can be obtained from ultra violet radiation and from various food sources. Cytochrome P450 enzymes are involved in the first step to regulate and process vitamin D in the human body.
Overall Structure
Cytochrome P450 exists as an . Each dimeric unit contains 12 α-helices (labeled A-L) along with β-sheets, which are mostly located on one side of the molecule. Helices F and G from each of the two units form the dimeric interface of cytochrome P450, and are also involved in the formation of the active site. This dimeric interface of the protein is stabilized by between the G helix of one the units with the F helix of the second unit, and vice versa. Two molecules of 2-hydroxypropyl-β-cyclodextrin, which is used to dissolve vitamin D3, are also found near the dimer interface.
Binding Interactions
The binding of Vitamin D3 occurs in a channel between the G and I helices and B' helix and B-C loop. In the you can see the residues that interact to bind Vitamin D3 and the channel between. Most of these residues are hydrophobic and thus have non polar interactions. Binding of the substrate causes the access channel to close. The B' helix has a flexible C terminus and can adopt a helix or loop conformation, which has van der waal interactions with the F-G loop. The B' helix unwinds outward to allow entrance of the substrate into the active site channel. CYP2R1 has an extended binding site where the access channel is part of the active site.
Additional Features
Cytochrome P45 has a central iron-bound heme, which, combined with its structural conformation, allows for hydroxylation with the attached substrate. Cytochrome P450 has specific vitamin D 25-hydroxylase activity, which does not function properly when a person has rickets. Rickets is caused when a person lacks sufficient vitamin D in their system, which is often caused by a vitamin D-25 hydroxylation defect. Leu99Pro is an evolutionarily conserved mutation in the beta helix which contributes to the hydroxylation defect. Leu99 does not inhibit substrate binding; however, Leu99Pro disturbs hydrogen binding around the heme and interferes with the helix steric properties, causing protein instability. When Leu99 does not have the proline mutation, its carboxyl group forms hydrogen bonds with Arg445 which are both located around the central heme.
Quiz Question 1
(merely an example of what this section might look like)
rom can you identify the green, red, and blue parts of the molecule?
See Also
Credits
Introduction - Sami Kriksceonaitis
Overall Structure - Kati Johnson
Drug Binding Site - Isabel Hand
Additional Features - Elizabeth Humble
Quiz Question 1 - Matthew Tiller1
References
- ↑ Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D3. J Mol Biol. 2008 Jun 27;380(1):95-106. Epub 2008 Apr 8. PMID:18511070 doi:10.1016/j.jmb.2008.03.065
