Structural insights into conformational stability of wild-type and mutant beta1-adrenergic receptor.

Biophysical Journal
Gouthaman S BalaramanNagarajan Vaidehi

Abstract

Recent experiments to derive a thermally stable mutant of turkey beta-1-adrenergic receptor (beta1AR) have shown that a combination of six single point mutations resulted in a 20 degrees C increase in thermal stability in mutant beta1AR. Here we have used the all-atom force-field energy function to calculate a stability score to detect stabilizing point mutations in G-protein coupled receptors. The calculated stability score shows good correlation with the measured thermal stability for 76 single point mutations and 22 multiple mutants in beta1AR. We have demonstrated that conformational sampling of the receptor for various mutants improve the prediction of thermal stability by 50%. Point mutations Y227A5.58, V230A5.61, and F338M7.48 in the thermally stable mutant m23-beta1AR stabilizes key microdomains of the receptor in the inactive conformation. The Y227A5.58 and V230A5.61 mutations stabilize the ionic lock between R139(3.50) on transmembrane helix3 and E285(6.30) on transmembrane helix6. The mutation F338M7.48 on TM7 alters the interaction of the conserved motif NPxxY(x)5,6F with helix8 and hence modulates the interaction of TM2-TM7-helix8 microdomain. The D186-R317 salt bridge (in extracellular loops 2 and 3) is stabilized...Continue Reading

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Citations

Nov 18, 2014·Journal of Chemical Theory and Computation·Supriyo BhattacharyaNagarajan Vaidehi
Aug 26, 2011·British Journal of Pharmacology·M WheatleyJ Barwell
May 24, 2013·The Journal of Physical Chemistry. B·Michiel J M NiesenNagarajan Vaidehi
Aug 14, 2019·Journal of Chemical Information and Modeling·Suvamay JanaNagarajan Vaidehi
Oct 26, 2018·Journal of Chemical Theory and Computation·Soumadwip GhoshNagarajan Vaidehi

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