Book of Abstracts: Albany 2009

category image Albany 2009
Conversation 16
June 16-20 2009
© Adenine Press (2008)

Side-Chain Dynamics in PDZ Domain Structure and Function

PDZ (post synaptic density-95, discs large, zo-1) domains are small, protein-protein binding modules that typically recognize C-terminal tail residues of target proteins. They are commonly found in multidomain signaling proteins and play a role in providing a scaffold for recruitment of multiple factors. We are using PDZ domains as models for the study of protein dynamics in function. NMR spectroscopy is ideally suited for characterizing molecular dynamics over a wide range of motional timescales. Analysis of 15N and 2H relaxation rates in several PDZ domains is beginning to reveal a role for picosecond-nanosecond motions in ligand binding. In particular, methyl containing side-chain motions can be quite sensitive to various perturbations to the domain. The dynamics are affected near and far from the perturbation and can result in significant changes in conformational entropy, which can result in significant modulation of binding affinity. These findings underscore the potential importance of dynamic allosteric regulation in proteins. Finally, comparison of the side-chain dynamics in multiple PDZ domains indicate that their dynamics are significantly conserved, suggesting further that nature uses dynamics, in addition to structure, as a means to achieve protein function.

Chad M. Petit1
Anthony B. Law2
Jun Zhang2
Ernesto J. Fuentes3
Andrew L. Lee1, 2

1Eshelman School of Pharmacy
Division of Medicinal Chemistry and Natural Products
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599
2Department of Biochemistry and Biophysics
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599
3Department of Biochemistry
University of Iowa
Iowa City, IA 52242

Phone: (919)-966-7821
Fax: (919)-843-5150
email Andrew Lee