Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site.

ABSTRACT: A common metabotropic glutamate receptor 5 (mGlu5) allosteric site is known to accommodate diverse chemotypes. However, the structural relationship between compounds from different scaffolds and mGlu5 is not well understood. In an effort to better understand the molecular determinants that govern allosteric modulator interactions with mGlu5, we employed a combination of site-directed mutagenesis and computational modeling. With few exceptions, six residues (P654, Y658, T780, W784, S808, and A809) were identified as key affinity determinants across all seven allosteric modulator scaffolds. To improve our interpretation of how diverse allosteric modulators occupy the common allosteric site, we sampled the wealth of mGlu5 structure-activity relationship (SAR) data available by docking 60 liga

SUBMITTER: Gregory KJ 

PROVIDER: S-EPMC3990945 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature