Dynamics-Driven Allostery in Protein Kinases.
Protein kinases have very dynamic structures and their functionality strongly depends on their dynamic state. Active kinases reveal a dynamic pattern with residues clustering into semirigid communities that move in μs-ms timescale. Previously detected hydrophobic spines serve as connectors between communities. Communities do not follow the traditional subdomain structure of the kinase core or its secondary structure elements. Instead they are organized around main functional units. Integration of the communities depends on the assembly of the hydrophobic spine and phosphorylation of the activation loop. Single mutations can significantly disrupt the dynamic infrastructure and thereby interfere with long-distance allosteric signaling that propagates throughout the whole molecule. Dynamics is proposed to be the underlying mechanism for allosteric regulation in protein kinases.
Department of Pharmacology, University of California at San Diego, La Jolla, CA, 92093, USA. Electronic address: akornev@ucsd.edu.
Alexandr P
AP
Kornev
Department of Pharmacology, University of California at San Diego, La Jolla, CA, 92093, USA; Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093, USA. Electronic address: staylor@ucsd.edu.
Susan S
SS
Taylor
D000494:Allosteric Regulation; D057927:Hydrophobic and Hydrophilic Interactions; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*
D011494:Protein Kinases
allostery; community analysis; protein dynamics; protein kinases