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Structural Biology 2018 & STD AIDS 2018
Journal of Genetics and Molecular Biology
|
Volume 2
S e p t e m b e r 0 3 - 0 4 , 2 0 1 8 | B a n g k o k , T h a i l a n d
allied
academies
STD-AIDS AND INFECTIOUS DISEASES
STRUCTURAL BIOLOGY AND PROTEOMICS
&
International Conference on
International Conference on
Joint Event on
Hong Xue et al., J Genet Mol Biol 2018, Volume 2
TOWARDS HIGH RESOLUTION GABAA
RECEPTOR MODULAR STRUCTURE
Hong Xue, Hoi Ming Li, Ata Ullah
and
Sue Tsang
Hong Kong University of Science and Technology, China
T
ype A gamma-butyric acid (GABAA) receptor is the main inhibitory
neurotransmitter receptor family in the brain. Previous studies including
those by us have associated GABAA receptor structural and functional
variations with neuropsychiatric disorders such as schizophrenia. Differential
expressions of alternative splicing isoforms of GABAA receptor beta-
2 subunit different in electrophysiology properties have been found in a
developmental stage and disease status dependent manner. High resolution
structural information is required to provide in-depth knowledge about the
mechanisms of associated neuropsychiatric disorders and a foundation for
structure-based drug development. To enable detailed structural studies, we
have previous established a platform for hyper expression and purification of
recombinant GABAA receptor proteins. By systematic deletions coupled with
secondary structure integrate analysis, two consecutive beta-rich structural
domains spanning the entirety of the extracellular region and a part of the
potential transmembrane portion of the receptor protein have been identified.
In addition, through site-directed Ala substitution of all non-Ala amino
acid residues within the second of the two domains, secondary structure
determinant and benzodiazepine binding site residues have been identified. A
beta-sandwich type of domain structure has been implicated from our series
of studies, which represents a discrepancy with the current structure model
of neurotransmitter-gated channel receptors. As a critical step in resolving
the recombinant GABAA receptor protein structure at atomic level, we have
recently achieved in sample preparation for Cryo-electromicroscopic analysis
(Figure 1). This will lead to high resolution structure for a important family of
neurotransmitter receptors pivotal in schizophrenia and comorbid disorders
and pave the way to new therapeutics for neuropsychiatric diseases.
Figure.1: Transmission electron micrographs of puri ed recombinant
protein fragments of GABAA receptor a1 subunit. (a) Electron micrograph of
negatively stained C166-L296 protein fragment; (b) electron micrograph of
negatively stained Q28-R248 protein fragment.
Recent Publications
1. Zhiwen Xu, Shisong Fang, Haifeng Shi, Hoiming Li, Jiun-Ming Wu, Hueih-
Min Chen, Yiqun Deng, Yinglei Liao, Hui Zheng,
Huaimin Zhu, Shui Ying Tsang and Hong
Xue (2005). Topology characterization of a
benzodiazepine-binding-rich domain of the
GABAA receptor α1 subunit. Protein Science
14: 2622 – 2637.
2. Haifeng Shi, Shui Ying Tsang, Man Kit Tse,
Zhiwen Xu andHong Xue (2003). Recombinant
extracellular domain of the three major
subunits of GABAA receptor show comparable
secondary structure and benzodiazepine
binding properties. Protein Sci. 12:2642-2646.
3. Jun Hang, Haifeng Shi, Dongyang Li, Yinglei
Liao, Dejun Lian, Yazhong Xiao, and Hong
Xue (2000). Ligand binding and structural
properties of segments of GABAA receptor α1
subunit overexpressed in Escherichia coli. J.
Biol. Chem. 275: 18818-18823.
4. Xue, H, H Zheng, HM Li, A Kitmitto, H Zhu, P
Lee and A Holzenburg (2000). A fragment
of recombinant GABAA receptor α1 subunit
forming rosette-like homo-oligomers. J. Mol.
Biol. 296: 739-742.
5. Xue, H, J Hang, R Chu, Y Xiao, H Li, P Lee, and
H Zheng (1999). Delineation of a membrane-
proximal β-rich domain in GABAA receptor by
progressive deletions. J. Mol. Biol. 285:55-61.
Hong Xue has obtained her first degree from the
Shanghai Second Military Medical University in 1983,
PhD from the Institute of Medical Sciences and De-
partment of Biochemistry, University of Toronto in
1992, and carried out postdoctoral studies at the De-
partment of Genetics, University of Glasgow before
joining the Department of Biochemistry, Hong Kong
University of Science and Technology (HKUST). Cur-
rently, she is Director of Applied Genomics Center of
HKUST and Professor of the Division of Life Science
at Hong Kong University of Science and Technology.
Her group research focuses on the type-A gamma
amino butyric acid (GABAA) receptor, the major inhibi-
tory neurotransmitter receptor, including the structure,
function, genetics and pharmacology aspects of GAB-
AA receptor and its involvement in neuropsychiatric
disorders such as schizophrenia.
hxue@ust.hkBIOGRAPHY