Ligand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor.
Nat Commun
; 14(1): 1179, 2023 03 02.
Article
en En
| MEDLINE
| ID: mdl-36859492
ABSTRACT
Biological regulation ubiquitously depends on protein allostery, but the regulatory mechanisms are incompletely understood, especially in proteins that undergo ligand-induced allostery with few structural changes. Here we used hydrogen-deuterium exchange with mass spectrometry (HDX/MS) to map allosteric effects in a paradigm ligand-responsive transcription factor, the lac repressor (LacI), in different functional states (apo, or bound to inducer, anti-inducer, and/or DNA). Although X-ray crystal structures of the LacI core domain in these states are nearly indistinguishable, HDX/MS experiments reveal widespread differences in flexibility. We integrate these results with modeling of protein-ligand-solvent interactions to propose a revised model for allostery in LacI, where ligand binding allosterically shifts the conformational ensemble as a result of distinct changes in the rigidity of secondary structures in the different states. Our model provides a mechanistic basis for the altered function of distal mutations. More generally, our approach provides a platform for characterizing and engineering protein allostery.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Espectrometría de Masas de Intercambio de Hidrógeno-Deuterio
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2023
Tipo del documento:
Article