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Structural Dynamics and Allosteric Signaling in Ionotropic Glutamate Receptors

Dutta, Anindita (2013) Structural Dynamics and Allosteric Signaling in Ionotropic Glutamate Receptors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate excitatory neurotransmission events in the central nervous system. All distinct classes of iGluRs (AMPA, NMDA, Kainate) are composed of an N-terminal domain (NTD) and a ligand-binding domain (LBD) in their extracellular domain, a transmembrane domain (TMD) and an intracellular carboxy-terminal domain (CTD). Ligand binding to the LBD facilitates ion channel activation. The NTDs modulate channel gating allosterically in NMDA receptors (NMDARs). A similar function of the NTD in AMPA receptors (AMPARs) is still a matter of debate. Taking advantage of recently resolved structures of the NTD and the intact AMPAR, the main focus of this dissertation is a comprehensive examination of iGluR NTD structural dynamics, ligand binding and allosteric potential of AMPARs. We use a multiscale, multi-dimensional approach using coarse-grained network models and all-atom simulations for structural analyses and information theoretic approaches for examination of evolutionary correlations. Our major contribution has been the characterization of the global motions favored by iGluR NTD architecture. These intrinsic motions favor ligand binding in NMDAR NTDs and are also shared by other iGluR NTDs. We also identified structural determinants of flexibility in AMPARs and confirmed their role through in silico mutants.
The overall similarity in collective dynamics among iGluRs hints at a putative allosteric capacity of non-NMDARs and has propelled the elucidation of interdomain and intersubunit coupling in the intact AMPAR. To this end, we identified “effector” and “sensor” regions in AMPARs using a perturbation-response technique. We identified potentially functional residues that enable information propagation between effector regions and proposed an efficient mechanism of allosteric communication based on a combination of tools including network models, graph theoretical methods and sequence analyses.
Finally, we assessed the “druggability” of iGluR NTDs using molecular dynamics simulations in the presence of probe molecules containing fragments shared by drug-like molecules. Based on our study, we offer key insights into the ligand-binding landscape of iGluR NTD monomers and dimers, and we also identify a novel ligand-binding site in AMPAR dimers. These findings open an avenue of searching for molecules able to bind to iGluR NTDs and allosterically modulate receptor activity.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dutta, Aninditaand77@pitt.eduAND77
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBahar, Ivetbahar@pitt.eduBAHAR
Committee ChairCarbonell,
Committee MemberGrabe, Michaelmdgrabe@pitt.eduMDGRABE
Committee MemberXie, Xiangqunxix15@pitt.eduXIX15
Committee MemberGreger,
Date: 16 December 2013
Date Type: Publication
Defense Date: 24 October 2013
Approval Date: 16 December 2013
Submission Date: 12 December 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 197
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational and Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Glutamate Receptors, Protein Dynamics, Elastic Network Models, Druggability, Sequence Coevolution, Allostreic Pathway
Date Deposited: 16 Dec 2013 16:13
Last Modified: 15 Nov 2016 14:16


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