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

This Article Full Text (PDF) All Versions of this Article: ps.051999206v1 15/5/1051    most recent Alert me when this article is cited Alert me if a correction is posted 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 Ozkirimli, E. Articles by Post, C. B. Search for Related Content PubMed PubMed Citation Articles by Ozkirimli, E. Articles by Post, C. B. Social Bookmarking                   What's this?

Src kinase activation: A switched electrostatic network

Medicinal Chemistry and Molecular Pharmacology Department, Markey Center for Structural Biology and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-2091, USA

(RECEIVED November 28, 2005; FINAL REVISION January 28, 2006; ACCEPTED January 31, 2006)

Src tyrosine kinases are essential in numerous cell signaling pathways, and improper functioning of these enzymes has been implicated in many diseases. The activity of Src kinases is regulated by conformational activation, which involves several structural changes within the catalytic domain (CD): the orientation of two lobes of CD; rearrangement of the activation loop (A-loop); and movement of an -helix (C), which is located at the interface between the two lobes, into or away from the catalytic cleft. Conformational activation was investigated using biased molecular dynamics to explore the transition pathway between the active and the down-regulated conformation of CD for the Src-kinase family member Lyn kinase, and to gain insight into the interdependence of these changes. Lobe opening is observed to be a facile motion, whereas movement of the A-loop motion is more complex requiring secondary structure changes as well as communication with C. A key result is that the conformational transition involves a switch in an electrostatic network of six polar residues between the active and the down-regulated conformations. The exchange between interactions links the three main motions of the CD. Kinetic experiments that would demonstrate the contribution of the switched electrostatic network to the enzyme mechanism are proposed. Possible implications for regulation conferred by interdomain interactions are also discussed.

Keywords: enzyme activation; protein electrostatics; activated molecular dynamics; allosterism; phosphoproteins

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051999206.

Abbreviations: CD, catalytic domain; SH2, Src homology domain 2; SH3, Src homology domain 3; CD_act, Lyn catalytic domain active conformation; CD_down, Lyn catalytic domain down-regulated conformation; N-lobe, N-terminal lobe; C-lobe, C-terminal lobe; MD, molecular dynamics; BMD, biased molecular dynamics; A-loop, activation loop; C, -helix C; RMSD, root mean squared deviation; , pairwise force constant.

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

This article has been cited by other articles:

				E. Ozkirimli, S. S. Yadav, W. T. Miller, and C. B. Post An electrostatic network and long-range regulation of Src kinases Protein Sci., November 1, 2008; 17(11): 1871 - 1880. [Abstract] [Full Text] [PDF]