Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble

Hong Pan, James Lee, Vincent J. Hilser

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

To explore how distal mutations affect binding sites and how binding sites in proteins communicate, an ensemble-based model of the native state was used to define the energetic connectivities between the different structural elements of Escherichia coli dihydrofolate reductase. Analysis of this model protein has allowed us to identify two important aspects of intramolecular communication. First, within a protein, pair-wise couplings exist that define the magnitude and extent to which mutational effects propagate from the point of origin. These pair-wise couplings can be identified from a quantity we define as the residue-specific connectivity. Second, in addition to the pair-wise energetic coupling between residues, there exists functional connectivity, which identifies energetic coupling between entire functional elements (i.e., binding sites) and the rest of the protein. Analysis of the energetic couplings provides access to the thermodynamic domain structure in dihydrofolate reductase as well as the susceptibility of the different regions of the protein to both small-scale (e.g., point mutations) and large-scale perturbations (e.g., binding ligand). The results point toward a view of allosterism and signal transduction wherein perturbations do not necessarily propagate through structure via a series of conformational distortions that extend from one active site to another. Instead, the observed behavior is a manifestation of the distribution of states in the ensemble and how the distribution is affected by the perturbation.

Original languageEnglish (US)
Pages (from-to)12020-12025
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number22
DOIs
StatePublished - Oct 24 2000

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Tetrahydrofolate Dehydrogenase
Binding Sites
Escherichia coli
Proteins
Thermodynamics
Point Mutation
Signal Transduction
Catalytic Domain
Ligands
Mutation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble. / Pan, Hong; Lee, James; Hilser, Vincent J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 22, 24.10.2000, p. 12020-12025.

Research output: Contribution to journalArticle

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