J Mol Biol. 1996 Mar 29;257(2):342-58.

An evolutionary trace method defines binding surfaces common to protein
families.

Lichtarge O, Bourne HR, Cohen FE.

Department of Cellular and Molecular Pharmacology, University of California San
Franciso, 94143-0450, USA.

X-ray or NMR structures of proteins are often derived without their ligands, and
even when the structure of a full complex is available, the area of contact that
is functionally and energetically significant may be a specialized subset of the
geometric interface deduced from the spatial proximity between ligands. Thus,
even after a structure is solved, it remains a major theoretical and
experimental goal to localize protein functional interfaces and understand the
role of their constituent residues. The evolutionary trace method is a
systematic, transparent and novel predictive technique that identifies active
sites and functional interfaces in proteins with known structure. It is based on
the extraction of functionally important residues from sequence conservation
patterns in homologous proteins, and on their mapping onto the protein surface
to generate clusters identifying functional interfaces. The SH2 and SH3 modular
signaling domains and the DNA binding domain of the nuclear hormone receptors
provide tests for the accuracy and validity of our method. In each case, the
evolutionary trace delineates the functional epitope and identifies residues
critical to binding specificity. Based on mutational evolutionary analysis and
on the structural homology of protein families, this simple and versatile
approach should help focus site-directed mutagenesis studies of
structure-function relationships in macromolecules, as well as studies of
specificity in molecular recognition. More generally, it provides an
evolutionary perspective for judging the functional or structural role of each
residue in protein structure.

Publication Types:
    Research Support, Non-U.S. Gov't 
    Research Support, U.S. Gov't, P.H.S. 

PMID: 8609628 [PubMed - indexed for MEDLINE]