| Autor: |
G D, Szklarz, S E, Graham, M D, Paulsen |
| Rok vydání: |
2000 |
| Předmět: |
|
| Zdroj: |
Vitamins and hormones. 58 |
| ISSN: |
0083-6729 |
| Popis: |
Cytochromes P450 are important heme-containing enzymes that catalyze the oxidation of a vast array of endogenous and exogenous compounds, including drugs and carcinogens. One of the more successful approaches to study P450 function involves molecular modeling. Because none of the mammalian P450s have been crystallized, a number of homology models have been constructed based on the structures of known bacterial P450s. Molecular models, generated using molecular replacement or distance geometry methods, can be used to dock substrates and/or inhibitors in the active site to explain various aspects of enzyme function. The majority of modeling research has dealt with enzyme-substrate interactions in the active site. The analysis of these interactions has helped us to better understand the mechanism of P450 catalysis and provided the structural basis for the regio- and stereospecificity of substrate oxidation as well as susceptibility to inhibition or inactivation. The models have been utilized to identify and/or confirm key residues and to rationally interpret experimental data. The alteration in activity in a mutant P450 can be related to changes in enzyme-substrate/inhibitor interactions, such as the removal or appearance of van der Waals overlaps or changes in compound mobility. Homology models can also help to analyze P450-redox partner interactions and identify critical determinants of protein stability. We can expect further development of molecular modeling methods and their increasing contribution into research on P450 function as an integral part of a combined theoretical-experimental approach. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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