Dataset Information

Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain.

ABSTRACT: The ionotropic glutamate receptors are localized in the pre- and postsynaptic membrane of neurons in the brain. Activation by the principal excitatory neurotransmitter glutamate allows the ligand binding domain to change conformation, communicating opening of the channel for ion conduction. The free energy of the GluR2 S1S2 ligand binding domain (S1S2) closure transition was computed using a combination of thermodynamic integration and umbrella sampling modeling methods. A path that involves lowering the charge on E705 was chosen to clarify the role of this binding site residue. A continuum electrostatics approach in S1S2 is used to show E705, located in the ligand binding cleft, stabilizes the closed conformation of S1S2 via direct interactions with other protein residues, not through the ligand. In the closed conformation, in the absence of a ligand, S1S2 is somewhat more closed than what has been reported in X-ray structures. A semiopen conformation has been identified which is characterized by disruption of a single cross-cleft interaction and differs only slightly in energy from the fully closed S1S2. The fully open S1S2 conformation exhibits a wide energy well and shares structural similarity with the apo S1S2 crystal structure. Hybrid continuum electrostatics/MD calculations along the chosen closure transition pathway reveal solvation energies, and electrostatic interaction energies between two lobes of the protein increase the relative energetic difference between the open and closed conformational states. By analyzing the role of several cross-cleft contacts as well as other binding site residues, we demonstrate how S1S2 interactions facilitate formation of the closed conformation of the GluR2 ligand binding domain.

SUBMITTER: Mamonova T

PROVIDER: S-EPMC2814871 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain.

Mamonova Tatyana T Yonkunas Michael J MJ Kurnikova Maria G MG

Biochemistry 20080930 42

The ionotropic glutamate receptors are localized in the pre- and postsynaptic membrane of neurons in the brain. Activation by the principal excitatory neurotransmitter glutamate allows the ligand binding domain to change conformation, communicating opening of the channel for ion conduction. The free energy of the GluR2 S1S2 ligand binding domain (S1S2) closure transition was computed using a combination of thermodynamic integration and umbrella sampling modeling methods. A path that involves low ...[more]

PMID: 18823129

Similar Datasets

Project description:BackgroundThe N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein-protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding cleft.ResultsThe existence of stable conformations in the left-handed helical and the extended regions of Tyr66 phi/psi space prevent rapid interconversion of the backbone and create a conformational switch such that Tyr66 in a left-handed helical backbone conformation results in an open cleft and in an extended backbone conformation results in a closed cleft. The stable conformations arise from deep, well-localized free-energy minima in the left-handed helical and extended regions of the Tyr66 phi/psi map. Changing the Tyr66 backbone conformation from extended to left-handed helical induces a closed-to-open transition in the cleft, and the reverse change in backbone conformation induces the reverse, open-to-closed transition. In the open-cleft state, weak solvent-exposed interactions involving the sidechains of Tyr66, Asp40, Lys55, and Gln57 serve to anchor the Tyr66 sidechain to the surface of the protein and away from the binding cleft entrance, thereby facilitating pY-peptide access to the binding cleft.ConclusionThe simulations point to a regulatory role for Tyr66 and surrounding residues in SHP-2 function: mutations at Tyr66, Asp40, Lys55, and/or Gln57 are predicted to break the switching mechanism and negatively impact pY-peptide binding. This in turn would interfere with cellular localization and the coupled SHP-2 phosphatase activity. The structurally well-defined binding cleft conformations resulting from the switch-like transition suggest the possibility of applying structure-based methods to develop inhibitors of N-SH2 pY-peptide binding to serve as research tools for signal transduction and precursors to therapeutics for SHP-2-related diseases.

Dataset Information

Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain.

Publications

Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets