Structural and functional studies of full-length receptor tyrosine kinases

Structural and functional studies of full-length receptor tyrosine kinases

Our major research program focuses on the structural and functional studies of receptor tyrosine kinases (RTKs), a family of cell surface receptors that play a key role in regulating normal cellular processes. Defects in RTK activation are causative in many cancers and other diseases and are targeted by many drugs. To date, many crystal structures for individual domains of RTKs are available. However, structural information on full-length RTKs, either in their apo- or ligand-bound multimeric states, has been elusive because these elongated and conformationally dynamic single-pass transmembrane proteins are difficult to crystalize. Thus, the central question of how information is relayed across plasma membrane by these important proteins remains unanswered. The RTK complexes have a molecular weight ranging from 140kDa to 800kDa, which makes them suitable for cryo-EM structural determination. Our lab is currently working on several members of RTK, including EGFR, RET, IR, and IGF1R. Solving the structures of different members of the RTK family will reveal similarities and differences in the structure-function relationships within this receptor family.

Collaborators

Xuewu Zhang, Hongtao Yu, Eunhee Choi

Related Publications

Daniel L Kober, Arun Radhakrishnan, Joseph L Goldstein, Michael S Brown, Lindsay D Clark, Xiao-chen Bai†, Daniel M Rosenbaum. Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing. Cell. 2021 Jul 8;184(14):3689-3701.e22.

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Emiko Uchikawa, Zhiming Chen, Guan-Yu Xiao, Xuewu Zhang, Xiao-chen Bai†. Structural basis of the activation of c-MET receptor. Nature Communications. 2021 Jul 1;12(1):4074.

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Defen Lu, Guijun Shang, Xiaojing He, Xiao-chen Bai†, Xuewu Zhang. Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex. Nature Communications. 2021 May 26;12(1):3172.

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Xiao-chen Bai†. Seeing Atoms by Single-Particle Cryo-EM. Trends in Biochemical Sciences. 2021 Apr;46(4):253-254.

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Byung-Cheon Jeong, Sung Jun Bae, Lisheng Ni, Xuewu Zhang, Xiao-chen Bai†, Xuelian Luo. Cryo-EM structure of the Hippo signaling integrator human STRIPAK. Nature Structural & Molecular Biology. 2021 Mar;28(3):290-299.

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Jie Yin, Kuang-Yui M Chen, Mary J Clark, Mahdi Hijazi, Punita Kumari, Xiao-chen Bai, Roger K Sunahara, Patrick Barth, Daniel M Rosenbaum. Structure of a D2 dopamine receptor–G-protein complex in a lipid membrane. Nature. 2020. Aug;584(7819):125-129.

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Yan Wang, Yan Han, Ji She, Nam X Nguyen, Vamsi K Mootha, Xiao-chen Bai, Youxing Jiang. Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter. eLife. 2020. Aug 7;9.

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Matthew Bratkowski, Tian Xie, Desiree A Thayer, Shradha Lad, Prakhyat Mathur, Yu-San Yang, Gregory Danko, Thomas C Burdett, Jean Danao, Aaron Cantor, Jennifer A Kozak, Sean P Brown, Xiaochen Bai, Shilpa Sambashivan. Structural and mechanistic regulation of the Pro-degenerative NAD hydrolase SARM1. Cell Reports. 2020. Aug 4;32(5):107999.

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Jing Xue, Tian Xie, Weizhong Zeng, Youxing Jiang, Xiao-chen Bai†. Cryo-EM structures of human ZnT8 in both outward- and inward-facing conformations. eLife. 2020. Jul 29;9.

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Xuewu Zhang, Xiao-chen Bai†, Zhijian J Chen†. Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity. 2020. Jul 14;53(1):43-53.

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Zhubing Shi, Haishan Gao, Xiao-chen Bai†, Hongtao Yu†. Cryo-EM structure of the human cohesin-NIPBL-DNA complex. Science. 2020. Jun 26;368(6498):1454-1459.

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Si Liu, Shenghai Chang, Binming Han, Lingyi Xu, Mingfeng Zhang, Cheng Zhao, Wei Yang, Feng Wang, Jingyuan Li†, Eric Delpire†, Sheng Ye†, Xiao-chen Bai†, Jiangtao Guo†. Cryo-EM structures of the human cation-chloride cotransporter KCC1. Science. 2019. Oct 25;366(6464):505-508.

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Jie Li*, Eunhee Choi*†, Hongtao Yu†, Xiao-chen Bai†. Structural basis of the activation of type 1 insulin-like growth factor receptor. Nature Communications 2019;10 (1), 1-11

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Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands
Jie Li*, Guijun Shang*, Yu-Ju Chen, Chad A Brautigam, Jen Liou, Xuewu Zhang†, Xiao-chen Bai†, eLife 2019;8: e47650.

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Emiko Uchikawa*, Eunhee Choi†*, Guijun Shang , Hongtao Yu†, Xiao-chen Bai†. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex. eLife 2019;8:e48630.

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