HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, B. Articles by McCammon, J. A. Search for Related Content PubMed PubMed Citation Articles by Lu, B. Articles by McCammon, J. A. Social Bookmarking                   What's this?

Release of ADP from the catalytic subunit of protein kinase A: A molecular dynamics simulation study

¹ Department of Chemistry and Biochemistry, ² Center for Theoretical Biological Physics, ³ Department of Pharmacology, ⁴ Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365, USA

(RECEIVED May 27, 2004; FINAL REVISION August 25, 2004; ACCEPTED August 25, 2004)

Substrate phosphorylation by cAMP-dependent-protein kinase A (protein kinase A, PKA) has been studied extensively. Phosphoryl transfer was found to be fast, whereas ADP release was found to be the slow, rate-limiting step. There is also evidence that ADP release may be preceded by a partially rate-limiting conformational change. However, the atomic details of the conformational change and the mode of ADP release are difficult to obtain experimentally. In this work, we studied ADP release from PKA by carrying out molecular dynamics simulations with different pulling forces applied to the ligand. The detailed ADP release pathway and the associated conformational changes were analyzed. The ADP release process was found to involve a swinging motion with the phosphate of ADP anchored to the Gly-rich loop, so that the more buried adenine base and ribose ring came out before the phosphate. In contrast to the common belief that a hinge-bending motion was responsible for the opening of the ligand-binding cleft, our simulations showed that the small lobe exhibited a large amplitude "rocking" motion when the ligand came out. The largest conformational change of the protein was observed at about the first quarter time point along the release pathway. Two prominent intermediate states were observed in the release process.

Keywords: ADP release; protein kinase A(PKA); hinge-bending motion; molecular dynamics pulling simulation

Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04894605.

Reprint requests to: J. Andrew McCammon, Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA; e-mail: blu{at}mccammon.ucsd.edu; fax: (858) 534-7042.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Bartova, J. Koca, and M. Otyepka Functional flexibility of human cyclin-dependent kinase-2 and its evolutionary conservation Protein Sci., January 1, 2008; 17(1): 22 - 33. [Abstract] [Full Text] [PDF]

				A. P. Kornev, N. M. Haste, S. S. Taylor, and L. F. Ten Eyck Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism PNAS, November 21, 2006; 103(47): 17783 - 17788. [Abstract] [Full Text] [PDF]

				Y. Cheng, Y. Zhang, and J. A. McCammon How does activation loop phosphorylation modulate catalytic activity in the cAMP-dependent protein kinase: A theoretical study Protein Sci., April 1, 2006; 15(4): 672 - 683. [Abstract] [Full Text] [PDF]