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Science 285 (5428): 756-760

Copyright © 1999 by the American Association for the Advancement of Science

Two-Metal-Ion Catalysis in Adenylyl Cyclase

John J. G. Tesmer, 1 Roger K. Sunahara, 2 Roger A. Johnson, 3 Gilles Gosselin, 4 Alfred G. Gilman, 2 Stephen R. Sprang 1*

Adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate, a ubiquitous second messenger that regulates many cellular functions. Recent structural studies have revealed much about the structure and function of mammalian AC but have not fully defined its active site or catalytic mechanism. Four crystal structures were determined of the catalytic domains of AC in complex with two different ATP analogs and various divalent metal ions. These structures provide a model for the enzyme-substrate complex and conclusively demonstrate that two metal ions bind in the active site. The similarity of the active site of AC to those of DNA polymerases suggests that the enzymes catalyze phosphoryl transfer by the same two-metal-ion mechanism and likely have evolved from a common ancestor.

1 Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA.
2 Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9041, USA.
3 Department of Physiology and Biophysics, Health Sciences Center, State University of New York, Stony Brook, NY 11794-8661, USA.
4 UMR CNRS-USTL 5625, Laboratoire de Chimie Bioorganique, Sciences et Techniques du Languedoc, Université Montpellier II, 34095 Montpellier, Cedex 5, France.
*   To whom correspondence should be addressed. E-mail: sprang{at}howie.swmed.edu


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