Biophysical Chem Lab Members Jeff Hoch Alan Stern Research LSIII Human Prolactin NMR Data Processing Macromolecular   Structure Calculations Group Alumni Peter Connolly Claudio Chuaqui Eric LaRosa Kuo-Bin Li George Maalouf John Osterhout Rowland Home

LSIII -- A "long neurotoxin" from the venom of Laticauda semifasciata

Peter J. Connolly, Alan S. Stern, and Jeffrey C. Hoch LSIII is a 66-residue protein which acts by binding to the nicotinic acetylcholine receptor, inducing paralysis. Structural investigations on LSIII are important because they can provide insights into the molecular details of its action, and reveal indirectly details of the structure of the acetylcholine receptor, for which only a low-resolution structure exists. We recently completed the determination of the solution structure by NMR, and are now pursuing investigations of the protein dynamics by relaxation experiments. The structure consists of three loops descending from a globular core that contains a two stranded beta-sheet. The central loop, which is known to be involved in binding to the receptor, appears to undergo a hinge-like rigid body motion. This observation contrasts with those of previous studies, which did not report local order in the loop. The dynamics of this loop holds several interesting implications for the nature of the receptor. Shown below is a superposition of a family of structures computed using distance restraints derived from nuclear Overhauser effects using restrained molecular dynamics calculations. The structures are aligned based on the structure of the well-ordered beta-sheet core of the protein. The apparent disorder at the bottom of the central (binding) loop can be seen to correspond to local order and a hinge-type motion of the loop, relative to the rest of the protein, by aligning just the loop portions. Below on the left are the superimposed loop regions, aligned as above, and on the right aligned using just the loop. This dynamical behavior of the loop relative to the rest of the protein is also evident in molecular dynamics simulations and C13 magnetic relaxation studies. Relevant publications "The Solution Structure of LSIII, a Long Neurotoxin from the Venom of Laticauda semifasciata" Peter J. Connolly, Alan S. Stern, and Jeffrey C. Hoch Biochemistry 35, 418-426 (1996) "Solution Structure of the Long Neurotoxin LSIII, With Possible Implications for Binding to the Acetylcholine Receptor" Peter J. Connolly, Alan S. Stern, and Jeffrey C. Hoch in Dynamics and the Problem of Recognition in Biological Macromolecules, O. Jardetzky and J.-F. Lefevre, Eds., Plenum Press, New York (1996) "Estimating Protein Fold from Incomplete and Approximate NMR Data" Peter J. Connolly, Alan S. Stern, and Jeffrey C. Hoch J. Am. Chem. Soc., 116, 2675-2676 (1994)