Mutations affecting the oligomerization interface of G-protein-coupled receptors revealed by a novel de novo protein design framework

Biophysical Journal
Martin S TaylorChristodoulos A Floudas

Abstract

Specific functional and pharmacological properties have recently been ascribed to G-protein-coupled receptor (GPCR) dimers/oligomers. Because the association of two identical or two distinct GPCR monomers seems to be required to elicit receptor function, it is necessary to understand the exact nature of this interaction. We present here a novel method for de novo protein design and its application to the prediction of mutations that can stabilize or destabilize a GPCR dimer while maintaining the monomer's native fold. To test the efficacy of this new method, the dimer of the single-spanned transmembrane domain of glycophorin A was used as a model system. Experimental data from mutagenesis of the helix-helix interface are compared with computational predictions at that interface, and the model's results are found to be consistent with the experimental findings. A flexible template was developed for the rhodopsin homodimer at atomic resolution and used to predict sets of three and five mutations. The results are found to be consistent across eight case studies, with favored mutations at each position. Mutation sets predicted to be the most disruptive at the dimerization interface are found to be less specific to the flexible temp...Continue Reading

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Citations

Aug 17, 2011·The Journal of Chemical Physics·D V S Ravikant, Ron Elber
Dec 7, 2010·Annual Review of Physical Chemistry·Ilan SamishJeffery G Saven
Nov 13, 2012·Annual Review of Pharmacology and Toxicology·Vsevolod KatritchRaymond C Stevens
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Nov 5, 2011·Biochimica Et Biophysica Acta·Jie LiangMeishan Lin
Jan 17, 2012·Structure·Jose Manuel Perez-Aguilar, Jeffery G Saven
May 21, 2010·Biophysical Journal·M L BellowsD Morikis
Jan 31, 2019·International Journal of Molecular Sciences·Yunhui PengSankar Basu

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