Molecular modelling of 17 alpha-hydroxylase-17,20-lyase

• Published in: Pharmazie Vol. 56; no. 6; p. 435
• Main Authors: Schappach, A, Höltje, H D
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2001
• Subjects: Amino Acid Sequence; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Steroid 17-alpha-Hydroxylase - chemistry; Substrate Specificity
• ISSN: 0031-7144

New methods in treatment of hormone-dependent diseases like prostate or breast cancer have become a major subject in medical and pharmaceutical research. Because of the direct correlation of cancer growth and hormone concentration inhibition of hormone biosynthesis reveals a promising strategy in cancer therapy. The key enzyme of androgen biosynthesis is the cytochrome P450 system 17 alpha-hydroxylase-17,20-lyase. To gain deeper insights into the structure and function of this enzyme, whose crystal structure is still unknown we present in this paper a theoretical 3D-model of the human 17 alpha-hydroxylase-17,20-lyase. The model was built by homology modelling using the crystal structure of the P450 CYPeryF as a template. After energy minimisation followed by molecular dynamics simulation the refined model exhibits reasonable protein geometry and a good protein folding quality. For evaluation of protein stability the structure was subjected to molecular dynamics in a waterbox under almost physiological conditions using the GROMACS program. The protein structure and folding remains stable even after 300 ps of free molecular dynamics simulation. The calculation of interaction fields employing the program GRID was used to characterise the active site of the protein. Subsequent docking studies with the natural substrate pregnenolone and further molecular dynamics of the protein-substrate-complexes enabled us to propose a putative binding-site for the physiological substrates.