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Structural basis of human cannabinoid CB1 G protein-coupled receptor activation

Scott, Caitlin Eileen and Abrol, Ravinder and Ahn, Kwang H. and Huang, Yuehan and Kendall, Debra A. and Goddard, William A., III (2013) Structural basis of human cannabinoid CB1 G protein-coupled receptor activation. FASEB Journal, 27 . Art. No. 831.4. ISSN 0892-6638.

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Transmembrane signal transduction is achieved by activation of G protein-coupled receptors (GPCRs) like the human cannabinoid CB1 receptor. These receptors exist in an ensemble of conformations, each of which might bind to different signaling molecules. Mutating a single residue, Thr 210, to Ile in the third transmembrane (TM3) domain, makes it more active then WT, whereas mutating it to Ala makes it fully inactive. We used the Gensemble method to predict 3D structures of these receptors. We find conformational differences that explain the CB1 receptor’s activation mechanism. These predictions were validated by designing double mutants that were expected to switch the inactive T210A back to WT levels of activation. The 2nd mutation for T210A is predicted to cause an important saltbridge between TMs 2 and 6 to break. GTPδ binding assays show a large increase in G protein-coupling for the double mutants indicating increased activation. We docked known agonists to these receptors and then performed 50 ns of molecular dynamics. The inactive T210A receptor with the docked agonist WIN55212 -2 maintains two stable interhelical salt-bridges. Similarly, the WT receptor maintains a salt-bridge between TMs 3 and 6, which suggests that a G protein is necessary to stabilize the active conformation.

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Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2013 FASEB. This work was funded by gifts from PharmSelex/Accelerator and NIH grants (R01NS071112, R01NS073115, R01AI040567, and DA020763).
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Record Number:CaltechAUTHORS:20130711-134311155
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39322
Deposited By: Tony Diaz
Deposited On:16 Jul 2013 21:44
Last Modified:03 Oct 2019 05:06

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