Theoretical study of the electrostatically driven step of receptor-G protein recognition

✍ Scribed by Francesca Fanelli; Cristina Menziani; Alexander Scheer; Susanna Cotecchia; Pier G. De Benedetti

• Book ID: 102648809
• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 751 KB
• Volume: 37
• Category: Article
• ISSN: 0887-3585
• DOI: 10.1002/(sici)1097-0134(19991101)37:2<145::aid-prot1>3.0.co;2-r

✦ Synopsis

This study proposes a theoretical model describing the electrostatically driven step of the ␣1b-adrenergic receptor (AR)-G protein recognition. The comparative analysis of the structuraldynamics features of functionally different receptor forms, i.e., the wild type (ground state) and its constitutively active mutants D142A and A293E, was instrumental to gain insight on the receptor-G protein electrostatic and steric complementarity. Rigid body docking simulations between the different forms of the ␣1b-AR and the heterotrimeric G␣q, G␣s, G␣i1, and G␣t suggest that the cytosolic crevice shared by the active receptor and including the second and the third intracellular loops as well as the cytosolic extension of helices 5 and 6, represents the receptor surface with docking complementarity with the G protein. On the other hand, the G protein solvent-exposed portions that recognize the intracellular loops of the activated receptors are the Nterminal portion of ␣3, ␣G, the ␣G/␣4 loop, ␣4, the ␣4/␤6 loop, ␣5, and the C-terminus. Docking simulations suggest that the two constitutively active mutants D142A and A293E recognize different G proteins with similar selectivity orders, i.e., G␣q Ա G␣s Ͼ G␣i Ͼ Ͼ G␣t. The theoretical models herein proposed might provide useful suggestions for new experiments aiming at exploring the receptor-G protein interface.