A comparative analysis of binding sites between mouse CYP2C38 and CYP2C39 based on homology modeling, molecular dynamics simulation and docking studies.
Mouse CYP2C38 and CYP2C39 are two closely related enzymes with 91.8% sequence identity. But they exhibit different substrate binding features. In this study, three-dimensional models of CYP2C38 and CYP2C39 were constructed using X-ray crystal structure of human CYP2C8 as the template based on homology modeling methods and molecular dynamics simulations. Tolbutamide as the common substrate of CYP2C38 and CYP2C39 was docked into them and positioned in their active sites with different orientation. All-trans retinoic acid (atRA) is a specific substrate for CYP2C39 and not catalyzed by CYP2C38. By comparison of active site architectures between CYP2C38 and CYP2C39, the possible reasons affecting their substrate binding were proposed. In addition, Arg241, Glu300, Leu366 and Leu476 are identified as critical residue for substrates binding.
State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
Xuan-Yu
XY
Meng
Qing-Chuan
QC
Zheng
Hong-Xing
HX
Zhang
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D000072516:Retinoic Acid 4-Hydroxylase; D017386:Sequence Homology, Amino Acid
D003577:Cytochrome P-450 Enzyme System; C542274:CYP2C38 protein, mouse; C000607083:Cyp2c39 protein, mouse; D000072467:Cytochrome P450 Family 2; D000072516:Retinoic Acid 4-Hydroxylase