Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

57-POS Board 17 Conformational Change of Dopamine D3 Receptor Complex Induces GDP Dissociation from Gai Protein for Signal Transmission Ya-Tzu Li , Hao-Jen Hsu. Tzu-Chi University, Hualien, Taiwan. G protein-coupled receptors (GPCRs), one of the largest superfamily of membrane proteins, can recognize most external stimuli in different signal transduction pathways responsible for a vast majority of physiological responses. Dopamine is an important neurotransmitter in the central nervous system that plays a critical role in movement, cognition and emotion. Dysfunction of dopamine receptors which belong to GPCR family A may lead to severe nervous diseases. In general, when dopamine binds to the dopamine receptor, it induces a conformational change of the receptor to recruit Ga protein association. GDP is then dissociated from Ga protein. However, the atomic-level activation mechanism of dopamine receptor from ligand binding to G protein dissociation for signal transmission remains unclear. In this research, based on our previous study, dopamine-bound full-length dopamine D3 receptor (D3R) with homology- modeled N-terminus taken from 1.8 µs MD simulations was docked to GDP-bound Gai for signal transmission during the activation. The multi-microsecond MD simulations showed that dopamine-Gai-GDP-bound D3R have large fluctuations in TMs 1, 3, 5 and 7 to enlarge the cytoplasmic binding site of D3R for Gai association. Helix a5 of Gai flatted to embed into ICL3 when compared with the dopamine-Gai-bound D3R complex system. The approach of helix a5 to ß6 of Gai and the flipping out of switch I and II of Gai may induce GDP dissociation from Gai. The internal water channel gradually formed during the D3R activation process, which is similar to other GPCRs. The findings of this study elucidate how D3R assumes its active conformation, and could prove valuable in drug design for the treatment of nervous system- related diseases.

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