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Druggability Simulations and X-ray Crystallography Reveal a Ligand-binding Site in the GluA3 AMPA Receptor N-terminal Domain

46 Pages Posted: 6 Jun 2018 Sneak Peek Status: Published

See all articles by Ji Young Lee

Ji Young Lee

University of Pittsburgh - Department Computational and Systems Biology

James Krieger

University of Pittsburgh - Department Computational and Systems Biology

Beatriz Herguedas

University of Cambridge - Neurobiology Division

Javier García-Nafría

University of Cambridge - Neurobiology Division

Anindita Dutta

University of Pittsburgh - Department Computational and Systems Biology

Saher A. Shaikh

University of Cambridge - Neurobiology Division

Ingo H. Greger

University of Cambridge - Neurobiology Division

Ivet Bahar

University of Pittsburgh - Department Computational and Systems Biology

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Abstract

Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission. Their dysfunction is implicated in several neurological disorders, rendering iGluRs potential drug targets. Here, we performed a systematic analysis of the druggability of two major iGluR subfamilies, using molecular dynamics simulations in the presence of drug-like molecules. We demonstrate the applicability of druggability simulations by faithfully identifying known agonist and modulator sites on AMPA receptors (AMPARs) and NMDA receptors. Simulations produced the expected allosteric changes of the AMPAR ligand-binding domain in response to agonist. We also identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), resulting from its unique conformational flexibility that we explored further with three new crystal structures trapped in vastly different states. In addition to providing novel insights into iGluR NTD dynamics, our approach identifies druggable sites and permits the determination of pharmacophoric features towards novel iGluR modulators.

Suggested Citation

Lee, Ji Young and Krieger, James and Herguedas, Beatriz and García-Nafría, Javier and Dutta, Anindita and Shaikh, Saher A. and Greger, Ingo H. and Bahar, Ivet, Druggability Simulations and X-ray Crystallography Reveal a Ligand-binding Site in the GluA3 AMPA Receptor N-terminal Domain (2018). Available at SSRN: https://ssrn.com/abstract=3188417 or http://dx.doi.org/10.2139/ssrn.3188417
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ji Young Lee

University of Pittsburgh - Department Computational and Systems Biology

Pittsburgh, PA 15260
United States

James Krieger

University of Pittsburgh - Department Computational and Systems Biology

Pittsburgh, PA 15260
United States

Beatriz Herguedas

University of Cambridge - Neurobiology Division

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Javier García-Nafría

University of Cambridge - Neurobiology Division

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Anindita Dutta

University of Pittsburgh - Department Computational and Systems Biology

Pittsburgh, PA 15260
United States

Saher A. Shaikh

University of Cambridge - Neurobiology Division

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Ingo H. Greger (Contact Author)

University of Cambridge - Neurobiology Division ( email )

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Ivet Bahar

University of Pittsburgh - Department Computational and Systems Biology ( email )

Pittsburgh, PA 15260
United States

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