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Computational Solvent Mapping Reveals the Importance of Local Conformational Changes for Broad Substrate Specificity in Mammalian Cytochromes P450†
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Section:Abstract
Computational solvent mapping moves small organic molecules as probes around a protein surface, finds favorable binding positions, clusters the conformations, and ranks the clusters on the basis of their average free energy. Prior mapping studies of enzymes, crystallized in either substrate-free or substrate-bound form, have shown that the largest number of solvent probe clusters invariably overlaps in the active site. We have applied this method to five cytochromes P450. As expected, the mapping of two bacterial P450s, P450 cam (CYP101) and P450 BM-3 (CYP102), identified the substrate-binding sites in both ligand-bound and ligand-free P450 structures. However, the mapping finds the active site only in the ligand-bound structures of the three mammalian P450s, 2C5, 2C9, and 2B4. Thus, despite the large cavities seen in the unbound structures of these enzymes, the features required for binding small molecules are formed only in the process of substrate binding. The ability of adjusting their binding sites to substrates that differ in size, shape, and polarity is likely to be responsible for the broad substrate specificity of these mammalian P450s. Similar behavior was seen at “hot spots” of protein−protein interfaces that can also bind small molecules in grooves created by induced fit. In addition, the binding of S-warfarin to P450 2C9 creates a high-affinity site for a second ligand, which may help to explain the prevalence of drug−drug interactions involving this and other mammalian P450s.
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This article has been cited by 4 ACS Journal articles (4 most recent appear below).
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Rapid Conformational Dynamics of Cytochrome P450 2E1 in a Natural Biological Membrane Environment
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Accession Codes
- PDB: 1BU7
- PDB: 1FAG
- PDB: 1PHC
- PDB: 1DZ4
- PDB: 1DT6
- PDB: 1NR6
- PDB: 1N6B
- PDB: 1SUO
- PDB: 1PO5
- PDB: 1OG2
- PDB: 1OG5
- PDB: 1R9O
- PDB: 1OG5X
History
- Published In Issue August 08, 2006
- Received February 18, 2006
Revised Manuscript Received June 2, 2006
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