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J. Biol. Chem., Vol. 282, Issue 13, 9748-9757, March 30, 2007

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The Molecular Basis for Cyclopiazonic Acid Inhibition of the Sarcoplasmic Reticulum Calcium Pump^*

From the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

The sarcoplasmic reticulum Ca²⁺-ATPase is essential for calcium reuptake in the muscle contraction-relaxation cycle. Here we present structures of a calcium-free state with bound cyclopiazonic acid (CPA) and magnesium fluoride at 2.65Å resolution and a calcium-free state with bound CPA and ADP at 3.4Å resolution. In both structures, CPA occupies the calcium access channel delimited by transmembrane segments M1–M4. Inhibition of Ca²⁺-ATPase is stabilized by a polar pocket that surrounds the tetramic acid of CPA and a hydrophobic platform that cradles the inhibitor. The calcium pump residues involved include Gln⁵⁶, Leu⁶¹, Val⁶², and Asn¹⁰¹. We conclude that CPA inhibits the calcium pump by blocking the calcium access channel and immobilizing a subset of transmembrane helices. In the E2(CPA) structure, ADP is bound in a distinct orientation within the nucleotide binding pocket. The adenine ring is sandwiched between Arg⁴⁸⁹ of the nucleotide-binding domain and Arg⁶⁷⁸ of the phosphorylation domain. This mode of binding conforms to an adenine recognition motif commonly found in ATP-dependent proteins.

Received for publication, December 20, 2006 , and in revised form, January 16, 2007.

^* This work was supported by grants from the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research, the Alberta Science and Research Investments Program, and the Canada Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2OA0 and 2O9J) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ Scholar of the Alberta Heritage Foundation for Medical Research and a New Investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Dept. of Biochemistry, University of Alberta, Medical Sciences Bldg. 327, Edmonton, Alberta T6G 2H7, Canada. Tel.: 780-492-3931; Fax: 780-492-0095; E-mail: hyoung{at}ualberta.ca.

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