Gearing up for GPCR activation
Researchers from the group of David Gloriam are honoured with the cover of Nature Structural & Molecular Biology.
ISBUC is proud to announce the publication of two back-to-back articles in Nature Structural & Molecular Biology by talented assistant professors, bioinformatician Albert Kooistra and data scientist Alexander Hauser from the group of David Gloriam in the Department of Drug Design and Pharmacology. The articles present a new online GPCR structure analysis platform and use it to perform a comparative analysis of inactive/active state structures, resulting in detailed molecular mechanistic maps of activation of the major GPCR classes. Experimental validation was done in collaboration with Stanford University, Université de Montréal and MRC Laboratory of Molecular Biology.
GPCR activation mechanisms across classes and macro/microscales
Two-thirds of human hormones and one-third of clinical drugs activate approximately 350 G-protein-coupled receptors (GPCRs). Here we show that, although they use the same structural scaffold and share several ‘helix macroswitches’, the GPCR classes differ in their ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.
Read the full article here in Nature Structural & Molecular Biology
An online GPCR structure analysis platform
This paper presents an online, interactive platform for comparative analysis of all available G-protein coupled receptor (GPCR) structures while correlating to functional data. The comprehensive platform encompasses structure similarity, secondary structure, protein backbone packing and movement, residue–residue contact networks, amino acid properties and prospective design of experimental mutagenesis studies. This lets any researcher tap the potential of sophisticated structural analyses enabling a plethora of basic and applied receptor research studies.
Read the full article here in Nature Structural & Molecular Biology.