Structural insights into G protein regulation

John J G Tesmer, Roger K. Snahara, Alfred G. Gilman, Stephen R. Sprang

Research output: Contribution to journalArticle

Abstract

The a subunit of the hcterotrirneric G protein Gs, when bound to GTP, activates all isoforms of adenyly! cyclase. 1 he crystal structure of the complex formed by GTP-4S-bound Gso and forskolin with the soluble, catalytic domains of adenylyl cyclase. has been determined. The catalytic site, at the interface between the (' i and C2 domains, was identified by diffusing the P-site inhibitor 2'deoxy, ii'AVIP in the presence of pyrophosphate and Mg2+ into the crystals. This site is distinct from that of the co-activator forskolin, which occupies a dyad-related site near that which accepts Gso. Acivation is induced by the insertion of the switch II helix of Gsa into a groove formed by two helices on the surface of the C2 domain near its intf-rface with the Cl domain. This event may trigger a reorientation of the Cl domain with respect to C2, thereby juxtaposing the catalytic Mg2+- and pyrophosphate-binding residues in Cl with the other elements of the ATI" binding site in C2. Introduction of the Psite analog into the active site is aiso accompanied by segmental conforational changes which mediate pyrophosphate binding. Comparison of the the structure of Gso with that of the inhibitory Gia subunit demonstrates that the latter is conformatiotially noncomplementary to the activator site of cyclase, despite overall conservation of residues in the switch II helix. Instead, Gia may bind cyrlase at a site on adonylyl ryrla&e that it dvad-reîated to that at which Gsa is bound.

Original languageEnglish (US)
Pages (from-to)A1324
JournalFASEB Journal
Volume12
Issue number8
StatePublished - Dec 1 1998

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Tesmer, J. J. G., Snahara, R. K., Gilman, A. G., & Sprang, S. R. (1998). Structural insights into G protein regulation. FASEB Journal, 12(8), A1324.