Coevolving residues distant from the ligand binding site are involved in GAF domain function.

ABSTRACT: Ligand binding to GAF domains regulates the activity of associated catalytic domains in various proteins, such as the cGMP-hydrolyzing catalytic domain of phosphodiesterase 5 (PDE5) activated by cGMP binding to GAFa domain. However, the specific residues involved and the mechanism of GAF domain function remain unclear. Here, we combine computational and experimental approaches to demonstrate that two highly coevolving residues, L267 and F295, distant from the ligand binding site, play a critical role in GAF domain allostery. Statistical Coupling Analysis (SCA) of GAF domain sequences identified these residues, and molecular dynamics (MD) simulations of both apo and holo forms of wild-type and mutant (L267A, F295A) PDE5 GAFa domains revealed significant changes in structural dynamics and cG

SUBMITTER: Ahmed WS 

PROVIDER: S-EPMC11977230 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature