Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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-ligand complexes. Here, we report high-resolution details of pronounced ∼1 ms time scale motions of a receptor-small 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-Purcell-Meiboom-Gill relaxation dispersion experiments and NOEs revealed the crystal structure to contain critical elements of the high energy protein-ligand conformation. The availability of accurate, structurally resolved dynamics in a protein-ligand complex should serve as a valuable benchmark for modeling dynamics in other receptor-ligand complexes and prediction of binding affinities.

Original languageEnglish (US)
Pages (from-to)6422-6428
Number of pages7
JournalJournal of the American Chemical Society
Issue number16
StatePublished - Apr 27 2011

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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