Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex.
J Am Chem Soc
; 133(16): 6422-8, 2011 Apr 27.
Article
em En
| MEDLINE
| ID: mdl-21469679
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidrofolato Desidrogenase
/
Receptores de Superfície Celular
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Estados Unidos