Dynamics of stromelysin/inhibitor interactions studied by 15N NMR relaxation measurements: Comparison of ligand binding to the S1-S3 and S′1-S′3 subsites
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This report describes the backbone amide dynamics of the uniformly 15N labeled catalytic domain of human stromelysin complexed to PNU-99533, a hydroxamate-containing ligand that binds to the S′1-S′3 region (right side) of the stromelysin active site, and to PNU-107859 and PNU-142372, both thiadiazole-containing ligands that bind to the S1-S3 region (left side) of the stromelysin active site. 15N R1, R2 and NOE NMR relaxation measurements were recorded and analyzed for each complex. Different dynamic behaviors were observed for stromelysin complexed to the two classes of ligands, indicating that it may be possible to use protein dynamics to distinguish between different binding orientations. In the absence of bound ligand at the S1-S3 subsites, the S1-S3 residues were found to be relatively rigid. In contrast, the S′1-S′3 subsites were found to be flexible in the absence of interactions with ligand. The relative rigidness of the S1-S3 subsites may be responsible for MMP binding specificity by discriminating between ligands of different shapes. By contrast, the inherent flexibility of the S′1-S′3 subsites allows structural rearrangement to accommodate a broad range of incoming substrates or inhibitors. Similarities and differences in dynamics observed for each complex provide insights into the interactions responsible for protein–ligand recognition. The relevance of protein dynamics to structure-based drug design is discussed.
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