QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.105.016691v1 mol.105.016691v2 69/1/11    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services 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 Arinaminpathy, Y. Articles by Biggin, P. C. Search for Related Content PubMed PubMed Citation Articles by Arinaminpathy, Y. Articles by Biggin, P. C.

Binding Site Flexibility: Molecular Simulation of Partial and Full Agonists within a Glutamate Receptor

Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, The University of Oxford, Oxford, United Kingdom

Ionotropic glutamate receptors mediate fast synaptic transmission in the mammalian central nervous system and play an important role in many different functions, including memory and learning. They have also been implicated in a variety of neuropathologies and as such have generated widespread interest in their structure and function. Molecular Dynamics simulations (5 x 20 ns) of the ligand-binding core of the GluR2 glutamate receptor were performed. Through simulations of both wild type and the L650T mutant, we show that the degree of protein flexibility can be correlated with the extent to which the binding cleft is open. In agreement with recent experiments, the simulations of kainate with the wild-type construct show a slight increase in -sheet content that we are able to localize to two specific regions. During one simulation, the protein made a transition from an open-cleft conformation to a closed-cleft conformation. This closed cleft conformation closely resembles the closed-cleft crystal structure, thus indicating a potential pathway for conformational change associated with receptor activation. Analysis of the binding pocket suggests that partial agonists possess a greater degree of flexibility within the pocket that may help to explain why they are less efficient at opening the channel than full agonists. Examination of water molecules surrounding the ligands reveals that mobility in distinct subsites can be a discriminator between full and partial agonism and will be an important consideration in the design of drugs against these receptors.

Address correspondence to: Dr. Philip Biggin, Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, The University of Oxford, South Parks Road, Oxford OX1 3QU, UK. E-mail: phil{at}biop.ox.ac.uk

This article has been cited by other articles:

				S. Amiri, M. S.P. Sansom, and P. C. Biggin Molecular dynamics studies of AChBP with nicotine and carbamylcholine: the role of water in the binding pocket Protein Eng. Des. Sel., July 1, 2007; 20(7): 353 - 359. [Abstract] [Full Text] [PDF]

				S. L. Kaye, M. S. P. Sansom, and P. C. Biggin Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-D-aspartate Receptor J. Biol. Chem., May 5, 2006; 281(18): 12736 - 12742. [Abstract] [Full Text] [PDF]