title: Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Carroll
authors.forename: Anna V
authors.initials: AV
authors.lastname: Gromova
authors.forename: Keith R
authors.initials: KR
authors.lastname: Miller
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
authors.forename: Xiang Simon
authors.initials: XS
authors.lastname: Wang
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathy
authors.forename: Scott F
authors.initials: SF
authors.lastname: Singleton
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Collins
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lee
mesh_terms: D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase