摘要：Macromolecular interactions such as estrogen receptor (ER)–a key driver of breast cancer growth–provide the molecular underpinning for virtually every biological process. Despite decades of effort, however, structure determination of protein-protein complexes is still a daunting task for existing techniques due to size, stability, and/or complexity of protein complexes of interest. To advance the ability to characterize these complexes, we have established a multi-technique iSPOT platform by integrating scattering, footprinting, and computational docking to determine a first median-resolution structure of the multi-domain ER complex. This knowledge reveals a completely new protein fold of ER that is different from that of existing hormone receptors, providing a glimpse into the hidden cross-talk between the ER domains critical for the design of next drugs, while the data-driven iSPOT development provides a vital step for biomedical applications to many protein-protein complexes for years to come.

报告人简介：

Sichun Yang

Center for Proteomics and Department of Nutrition, Department of Pharmacology, Department of Physiology and Biophysics,

Case Western Reserve University School of Medicine

Cleveland, OH 44106

phone (216) 368 5793

email sichun.yang@case.edu

web www.theyanglab.org

Biography

Dr. Sichun Yang started his biophysical research at the University of California San Diego after receiving B.S. and M.S. in Physics from China. He obtained a Ph.D. in Biophysics from UCSD on September 9th, 2006. His PhD research with Dr. Herbert Levine and Dr. Jose Onuchic (both now at Rice) focused on protein folding and protein-protein assembly, from the perspective of computer simulation and statistical mechanics. In 2006-2010, Dr.Yang carried out his postdoctoral research with Dr. Benoit Roux at the Department of Biochemistry and Molecular Biology at the University of Chicago. He began to bridge computation and experiment and demonstrated that combining computer simulation and synchrotron X-ray scattering is ideally positioned to study the structural dynamics of bimolecular complexes (PNAS, 2010). This work has been featured in a News & Views article (Nature, 2010). In collaboration with Dr. Geof Greene at UChicago, Dr. Yang began to work on the molecular biophysics of estrogen receptor (ER), a key molecule in breast cancer biology, and had received a prestigious idea award from the Department of Defense.

Dr. Yang joined the School of Medicine at Case Western Reserve University in 2010. Since then, he has been focusing on basic and translational studies of estrogen receptor (ER), ranging from fundamental biophysics to drug discovery. With a recent 5-year NIH R01 support (as well as DoD, ACS and CTSC), he has developed a powerful integrated multi-biophysical platform, termed iSPOT (i.e., the integration of Small-angle scattering, hydroxyl radical footPrinting, and dOcking simulaTion). We have provided a principle-of-principle demonstration on well-studied molecular systems and more importantly, a realistic application to solving a first mediate-resolution structure of ER, a key molecule in breast cancer biology. Also, Dr. Yang has been actively researching the folding of an intrinsically disordered domain of the ER to understand the role of such a protein folding phenomena in cancer activation. His contribution in algorithms and methods development (e.g., Fast-SAXS-pro, protection factor analysis, and iSPOT) leads to collaboration with computational and experimental biophysicists here at Cleveland and other parts of the globe.

Selected Publications: 

Thermodynamics of Hydrophobic Amino Acids in Solution: A Combined Experimental-Computational Study

Journal of Physical Chemistry Letters 8 347–351 (2017)

Lingshuang Song, Lin Yang, Jie Meng, and S. Yang

Structural basis of ligand interaction with atypical chemokine receptor 3

Nature Communications 8 14125 (2017)

Martin Gustavsson, Liwen Wang, Noortje van Gils, Bryan S. Stephens, Penglie Zhang, Thomas J. Schall, S. Yang, Ruben Abagyan, Mark R. Chance, Irina Kufareva, and Tracy M. Handel  

Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking

Journal of Structural Biology 196 (3) 340-349 (2016)

Wei Huang, Krishna M Ravikumar, Marc Parisien, and S. Yang

SAXS-driven Computational Modeling of Biomolecular Complexes

Wiley-VCH Verlag, (2016)

L. Song, L. Lu, W. Huang, K.M. Ravikuma, J. Meng, S. Yang 

Accurate optimization of amino acid form factors for computing small-angle X-ray scattering intensity of atomistic protein structures

Journal of Applied Crystallography, 49 (4) 1148-1161 (2016)

D. Tong, S. Yang, and L. Lu

Improved accuracy of high-q regions in SAXS computing 

Quantitative protein topography analysis and high-resolution structure prediction using hydroxyl radical labeling and tandem-ion mass spectrometry

Mol Cell Proteomics, 14 (4) 1159–1168 (2015)

Parminder Kaur, Janna Kiselar, S. Yang, and Mark Chance

Quantitative mapping of protein structure by hydroxyl radical footprinting mediated structural mass spectrometry: A protection factor analysis

Biophys. J., 108 (1) 107–115 (2015)

Wei Huang, Krishna M Ravikumar, Mark Chance, and S. Yang 

A Newfound Cancer-activating Mutation Reshapes the Energy Landscape of Estrogen-binding Domain

Journal of Chemical Theory and Computation, 10 (8) 2897–2900, (2014)

Wei Huang, Krishna M Ravikumar, and S. Yang

Methods for SAXS-based Structure Determination of Biomolecular Complexes

Advanced Materials, 26 7902–7910, (2014)

S. Yang (Invited Review - Research News)

Cross-talk between the ligand- and DNA-binding domains of estrogen receptor

PROTEINS, 81 (11) 1900-1909, (2013)

Wei Huang, Geoffrey L Greene, Krishna M Ravikumar, and Sichun Yang

Energy evaluation of β-strand packing in a fibril-forming SH3 domain

J. Phys. Chem. B, 117 (42) 13051–13057, (2013)

Sichun Yang*, Krishna M Ravikumar, and Herbert Levine* 

Fast-SAXS-pro: A unified approach to computing SAXS profiles of DNA, RNA, protein, and their complexes

J. Chem. Phys.138 (2) 024112 (7 pages), (2013)

Krishna M Ravikumar, Wei Huang and Sichun Yang

Identification of a novel LXXLL motif in alpha actinin 4 (ACTN4) spliced isoform that is critical for its interaction with estrogen receptor alpha and co-activators

J. Biol. Chem. 287 (42), 35418-35429, (2012)

Simran Khurana, Sharmistha Chakraborty, Xuan Zhao, Yu Liu, Dongyin Guan, Minh Lam, Wei Huang, Sichun Yang and Hung-Ying Kao

Coarse-Grained Simulations of Protein-Protein Association: An Energy Landscape Perspective

Biophys. J.103 (4) 837–845 (2012)

Krishna M Ravikumar, Wei Huang and Sichun Yang

Introduced the pull-push-release (PPR) sampling algorithm for the simulations of protein-protein interactions.

EROS: Better than SAXS!

Structure. 19 (1), 3-4 (2011)

Sichun Yang and Benoît Roux

Multidomain Assembled States of Hck Tyrosine Kinase in Solution

Proc. Natl. Acad. Sci. USA 107, 15757-15762 (2010)

Sichun Yang, Lydia Blachowicz, Lee Makowski, and Benoît Roux

Featured in a News & Views article by Bernadó and Blackledge in Nature (2010).

Structural biology: Proteins in dynamic equilibrium

Nature 468, 1046-1048 (2010)

RNA Structure Determination Using SAXS Data

J. Phys. Chem. B. 114 (31), 10039-10048 (2010)

Sichun Yang, Marc Parisien, François Major, and Benoît Roux

Atomistic view of the conformational activation of Src kinase using the string method with swarms-of-trajectories

Biophysical Journal 97,(4) L8-L10 (2009)

Wenxun Gan, Sichun Yang, and Benoît Roux

A rapid coarse residue-based computational method for X-ray solution scattering characterization of protein folds and multiple conformational states of large protein complexes

Biophysical Journal 96, 4449-4463 (2009)

Sichun Yang, Sanghyun Park, Lee Makowski, and Benoît Roux

Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories

Proc. Natl. Acad. Sci. USA 106, 3776-3781 (2009)

Sichun Yang, Nilesh K. Banavali, and Benoît Roux

Src kinase conformational activation: Thermodynamics, pathways, and mechanisms

PLoS Computational Biology 4, e1000047 (14 pages) (2008)

Sichun Yang and Benoît Roux

Folding time predictions from all-atom replica exchange simulations

J. Mol. Biol. 372, 756-763 (2007)

Sichun Yang, José N. Onuchic, Angel E. García, and Herbert Levine

Effective stochastic dynamics on a protein folding energy landscape

J. Chem. Phys. 125, 054910 (8 pages) (2006)

Sichun Yang, José N. Onuchic, and Herbert Levine

Prion disease: Exponential growth requires membrane binding

Biophys. J. 90, L77-L79 (2006)

Daniel L. Cox, Rajiv R. P. Singh, and Sichun Yang

Structure of infectious prions: Stabilization by domain swapping

FASEB. J. 19, 1778-1782 (2005)

Sichun Yang, Herbert Levine, José N. Onuchic, and Daniel L. Cox

Protein oligomerization through domain swapping: Role of inter-molecular interactions and protein concentration

J. Mol. Biol. 352, 202-211 (2005)

Sichun Yang, Herbert Levine, and José N. Onuchic

Domain swapping is a consequence of minimal frustration

Proc. Natl. Acad. Sci. USA 101, 13786-13791 (2004)

Sichun Yang*, Samuel S. Cho*, Yaakov Levy, Margaret S. Cheung, Herbert Levine, Peter G. Wolynes, and José N. Onuchic