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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
92
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.