Direct Detection of Structurally Resolved Dynamics in a Multiconformation Receptor鈭扡igand Complex

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• 作者：Mary J. Carroll ; Anna V. Gromova ; Keith R. Miller ; Hao Tang ; Xiang Simon Wang ; Ashutosh Tripathy ; Scott F. Singleton ; Edward J. Collins ; Andrew L. Lee
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：April 27, 2011
• 年：2011
• 卷：133
• 期：16
• 页码：6422-6428
• 全文大小：892K
• 年卷期：v.133,no.16(April 27, 2011)
• ISSN：1520-5126

文摘

Structure-based drug design relies on static protein structures despite significant evidence for the need to include protein dynamics as a serious consideration. In practice, dynamic motions are neglected because they are not understood well enough to model, a situation resulting from a lack of explicit experimental examples of dynamic receptor鈭抣igand complexes. Here, we report high-resolution details of pronounced 1 ms time scale motions of a receptor鈭抯mall molecule complex using a combination of NMR and X-ray crystallography. Large conformational dynamics in Escherichia coli dihydrofolate reductase are driven by internal switching motions of the drug-like, nanomolar-affinity inhibitor. Carr鈭扨urcell鈭扢eiboom鈭扜ill relaxation dispersion experiments and NOEs revealed the crystal structure to contain critical elements of the high energy protein鈭抣igand conformation. The availability of accurate, structurally resolved dynamics in a protein鈭抣igand complex should serve as a valuable benchmark for modeling dynamics in other receptor鈭抣igand complexes and prediction of binding affinities.