STRUCTURAL CHARACTERIZATION AND CONFORMATIONAL DYNAMICS OF CLAMSHELL-LIKE LIGAND-BINDING DOMAINS

glutamate receptors;iGluR;umbrella sampling;odorant receptors;mGluR;glutamate;LBD;Biophysics

Wied, Tyler JohnWolberger, Cynthia ;

Johns Hopkins University

关键词: glutamate receptors;    iGluR;    umbrella sampling;    odorant receptors;    mGluR;    glutamate;    LBD;    Biophysics;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60096/WIED-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Clamshell-like ligand binding domains (LBDs) are a diverse class of receptors presentin all clades of life. Ligands bind to a cleft which facilitates a transition from primar-ily open conformations to closed conformations. The LBDs bind a diverse array ofligands, and exhibit large conformational heterogeneity. This dissertation examinesthe structure and conformational dynamics of three clamshell-like LBDs, each from adifferent protein system: ionotropic glutamate receptors (iGluRs), metabotropic glu-tamate receptors (mGluRs), and ionotropic receptors (IRs). In Chapter 1, I reviewvarious clamshell-like LBD types and discuss their structure, function, and dynam-ics. Chapter 2 introduces molecular dynamics simulation and contains a generalprotocol for users to set up a similar system on their own. Chapter 3 reveals thatthe iGluR GluK2, a kainate receptor, has remarkable conformational flexibility. Wealso present agreement between theoretical and experimental results. Chapter 4examines the conformational free energies of mGluR3 in monomer and dimer states,and reveals an interesting effect of dimerization on the stability of closed state LBDs.Finally, Chapter 5 discusses initial attempts to express and purify insect odorantreceptor IR LBDs. Together, this work advances our understanding of LBDs acrossa spectrum of receptor families.