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Science 12 December 1997:
Vol. 278. no. 5345, pp. 1907 - 1916
DOI: 10.1126/science.278.5345.1907
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Research Articles

Crystal Structure of the Catalytic Domains of Adenylyl Cyclase in a Complex with Gsalpha·GTPgamma S

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

The crystal structure of a soluble, catalytically active form of adenylyl cyclase in a complex with its stimulatory heterotrimeric G protein alpha  subunit (Gsalpha ) and forskolin was determined to a resolution of 2.3 angstroms. When P-site inhibitors were soaked into native crystals of the complex, the active site of adenylyl cyclase was located and structural elements important for substrate recognition and catalysis were identified. On the basis of these and other structures, a molecular mechanism is proposed for the activation of adenylyl cyclase by Gsalpha .

J. J. G. Tesmer and S. R. Sprang are at the Howard Hughes Medical Institute and the Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA. R. K. Sunahara and A. G. Gilman are in the Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9041, USA.

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Interaction with Gbeta gamma Is Required for Membrane Targeting and Palmitoylation of Galpha s and Galpha q.
D. S. Evanko, M. M. Thiyagarajan, and P. B. Wedegaertner (2000)
J. Biol. Chem. 275, 1327-1336
   Abstract »    Full Text »    PDF »
Enzymatic Synthesis of Unlabeled and beta -32P-labeled beta -L-2',3'-Dideoxyadenosine-5'-triphosphate as a Potent Inhibitor of Adenylyl Cyclases and Its Use as Reversible Binding Ligand.
I. Shoshani, V. Boudou, C. Pierra, G. Gosselin, and R. A. Johnson (1999)
J. Biol. Chem. 274, 34735-34741
   Abstract »    Full Text »    PDF »
Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents.
I. Shoshani, W. H. G. Laux, C. Perigaud, G. Gosselin, and R. A. Johnson (1999)
J. Biol. Chem. 274, 34742-34744
   Abstract »    Full Text »    PDF »
Covalent Labeling of Adenylyl Cyclase Cytosolic Domains with gamma -Methylimidazole-2',5'-dideoxy-[gamma -32P]3'-ATP and the Mechanism for P-site-mediated Inhibition.
S. Doronin, L. Murray, C. W. Dessauer, and R. A. Johnson (1999)
J. Biol. Chem. 274, 34745-34750
   Abstract »    Full Text »    PDF »
Gsalpha Repression of Adipogenesis via Syk.
H.-y. Wang and C. C. Malbon (1999)
J. Biol. Chem. 274, 32159-32166
   Abstract »    Full Text »    PDF »
Activating Mutation of Adenylyl Cyclase Reverses its Inhibition by G Proteins.
G. Zimmermann, D. Zhou, and R. Taussig (1999)
Mol. Pharmacol. 56, 895-901
   Abstract »    Full Text »
Physiological Regulation of G Protein-Linked Signaling.
A. J. Morris and C. C. Malbon (1999)
Physiol Rev 79, 1373-1430
   Abstract »    Full Text »    PDF »
The N Terminus Domain of Type VI Adenylyl Cyclase Mediates Its Inhibition by Protein Kinase C.
H.-L. Lai, T.-H. Lin, Y.-Y. Kao, W.-J. Lin, M.-J. Hwang, and Y. Chern (1999)
Mol. Pharmacol. 56, 644-650
   Abstract »    Full Text »
Regulation of beta -Adrenoceptor Signaling in Cardiac Function and Disease.
N. Dzimiri (1999)
Pharmacol. Rev. 51, 465-502
   Abstract »    Full Text »    PDF »
Amplification of the Cyclic AMP Response to Forskolin in Pheochromocytoma PC12 Cells through Adenosine A2A Purinoceptors.
C. Florio, F. Frausin, R. Vertua, and R. M. Gaion (1999)
J. Pharmacol. Exp. Ther. 290, 817-824
   Abstract »    Full Text »
Two-Metal-Ion Catalysis in Adenylyl Cyclase.
J. J. Tesmer, R. K. Sunahara, R. A. Johnson, G. Gosselin, A. G. Gilman, and S. R. Sprang (1999)
Science 285, 756-760
   Abstract »    Full Text »
Adenylyl Cyclase, a Coincidence Detector for Nitric Oxide.
M. McVey, J. Hill, A. Howlett, and C. Klein (1999)
J. Biol. Chem. 274, 18887-18892
   Abstract »    Full Text »    PDF »
Structure of Gialpha 1·GppNHp, Autoinhibition in a Galpha Protein-Substrate Complex.
D. E. Coleman and S. R. Sprang (1999)
J. Biol. Chem. 274, 16669-16672
   Abstract »    Full Text »    PDF »
The alpha -Helical Domain of Galpha t Determines Specific Interaction with Regulator of G Protein Signaling 9.
N. P. Skiba, C.-S. Yang, T. Huang, H. Bae, and H. E. Hamm (1999)
J. Biol. Chem. 274, 8770-8778
   Abstract »    Full Text »    PDF »


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