Protein Dynamics, Ligand Binding, and Biological Function

Dynamics is essential for protein function. To demonstrate this point, this talk presents three studies. (1) For a ligand-gated ion channel, ligand binding leads to channel activation by modulating the dynamics of the channel protein. A common theme that emerges from different families of ligand-gated ion channels is that agonist binding closes the ligand-bidning domain (LBD), leading to pore opening in the transmembrane domain (TMD); in contrast, antagonist binding opens the LBD, leading to pore closing in the TMD [1]. (2) When the structure [2] and gating dynamics [3] of the influenza M2 proton channel are accounted for, the calculated rate of ion transport is in quantitative agreement with experimental data [4]. (3) In enzymes, gating dynamics afford substrate selectivity [5]. \\[4pt] [1] M. Yi, H. Tjong, and H.-X. Zhou (2008). Spontaneous conformational change and toxin binding in $\alpha $7 nicotinic acetylcholine receptor: insight into channel activation and inhibition. Proc. Natl. Acad. Sci. 105, 8280-8285. \\[0pt] [2] M. Sharma, M. Yi, H. Dong, H. Qin, E. Peterson, D. D. Busath, H.-X. Zhou, and T. A. Cross (2010). Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer. Science 330, 509-512. \\[0pt] [3] M. Yi, T. A. Cross, and H.-X. Zhou (2009). Conformational heterogeneity of the M2 proton channel and a structural model for channel activation. Proc. Natl. Acad. Sci. USA 106, 13311-13316. \\[0pt] [4] H.-X. Zhou (2010). Diffusion-influenced transport of ions across a transmembrane channel with an internal binding site. J. Phys. Chem. Lett. 1, 1973-1976. \\[0pt] [5] H.-X. Zhou, S. T. Wlodek, and J. A. McCammon (1998). Conformation gating as a mechanism for enzyme specificity. Proc. Natl. Acad. Sci. USA 95, 9280-9283.