苏晓东 教授
结构生物学组
北京大学 生命科学学院 教授，博士生导师
电话：
E-mail：xdsu@pku.edu.cn
1、利用X-射线晶体学手段研究细胞信号传导机制相关的蛋白质及其复合物结构，特别是固有免疫及DNA与蛋白质的相互作用复合物的研究；
2、运用单分子荧光成像技术等生物物理方法研究DNA-蛋白质的相互作用；
3、基于结构的蛋白质工程及药物（蛋白和小分子药物）设计方法及应用，特别是针对肿瘤的诊断、抗体治疗及药物设计研究；
4、发展NGS（新一代）DNA测序技术及生物信息学分析大数据，进行癌症（特别是脑胶质瘤）的基因组测序及生物信息挖掘研究，提出病因、肿瘤标志物及治疗的新方案。
STING基因突变会引起严重的自身免疫疾病STING-associated vasculopathy with onset in infancy, SAVI。致病突变在蛋白序列上表现为V147L、N154S或V155M。这些突变会使病人体内STING处于过度激活状态，导致I型干扰素持续高表达。细胞实验表明STING的V147L、N154S、V155M突变体在没有cGAMP的情况下就处于激活状态，而加入cGAMP之后活性却没有进一步提高。目前对于SAVI没有有效治疗手段，抑制STING的持续性激活是寻找SAVI治疗手段的主要潜在方向。
解析了STING致病突变体CTD的apo以及结合cGAMP复合物的晶体结构，发现STING突变体在apo状态下处于“开放”构象，结合cGAMP之后转变为“闭合”构象，与野生型相同。等温滴定量热实验表明STING突变体仍可以结合cGAMP，结合常数与野生型略有不同。通过序列比对及结构和功能分析，发现致病突变所在的140-155这一段序列高度保守，连接跨膜区和C端可溶性区域，对于STING的功能非常重要。推测140-155这一段区域的作用是在STING未被激活的情况下与CTT相互作用并将其固定住，STING结合CDNs被激活之后，CTT被释放，磷酸化位点暴露出来，进而与TBK1、IRF3相互作用，而V147L N154S V155M突变影响了与CTT的相互作用，使得CTT在STING没有结合CDNs的情况下就释放出来，激活下游信号。
通过基于结构的分析找到了能使hSTING识别作为抗癌药物筛选出来的一个黄酮类小分子DMXAA的单点突变，为hSTING 激动剂的合理化设计提供基础。同时通过分析STING致病突变体，提出STING的激活机制模型，阐述了致病机理，为STING抑制剂的研究及自身免疫疾病的治疗提供思路。
DNA甲基化对转录因子结合的影响以及对后续转录调控的贡献的研究。DNA的甲基化是生物体表观遗传学修饰中非常重要的一种调控方式。本实验室从几种重要真核生物转录因子GR，ER和BMAL1/CLOCK入手，运用单分子荧光技术，ITC等方法研究了它们与各自结合序列的非甲基化状态和甲基化状态之间的亲和力和结合稳定性的不同。结果发现DNA胞嘧啶的甲基化是可以调控蛋白质与DNA的相互作用的，但是其调控的方向，以及程度都会因为具体蛋白的不同而呈现不同的方式。我们同时通过细胞实验证实了这种调控可以继续在蛋白表达水平上体现出来，因此这种调控是具有生理意义的。
通过X-ray晶体学和结构生物学的方法研究了GRDBD与不同甲基化的GRE的三个复合物之间的相互作用，以期进一步了解这种相互作用的改变机制。研究发现，胞嘧啶的甲基化确实可以在某些特殊的地方改变DNA和蛋白质的相互作用图谱，但是其胞嘧啶的甲基位置与蛋白质完全没有相互作用。这启示我们，甲基化的调控机制很有可能是通过改变DNA的结构或者结构的稳定性来调控DNA-蛋白质相互作用。为研究这种调控机制，我们和化学院高毅勤教授合作，运用MD模拟计算的方法分别计算了这些复合物的DNA中双碱基对序列之前的堆叠面积的变化。分析结果显示，胞嘧啶甲基化可以调节双碱基对之间的堆叠面积。而堆叠面积的变化也侧面反映出了DNA整体结构的柔性变化。这意味着DNA的甲基化是通过改变DNA的整体结构来影响其与蛋白质相互作用的。
为进一步探讨这种甲基化对蛋白质结合的影响是否会直接影响这些转录因子在基因组上对结合位点的选择，我们采用免疫共沉淀-甲基化测序技术对GR和BMAML1-CLOCK进行了研究。结果发现GR在基因组上不但能结合甲基化水平低的位点，还能结合甲基化水平高的位点。这是由于GR识别序列的甲基化不会减弱其与GR的相互作用，相反，还有增强作用。而BMAL1-CLOCK则不同，它只能结合低甲基化的序列，这是由于其识别序列的甲基化能减弱其相互作用所致。
Zhang TZ, Shi C, Ye ZY, Deng J, Gu MY, Chen ZX, Huang LX, Su XD, Chang ZZ. (2024) Crystal structure combined with metabolomics and biochemical studies indicates that FAM3A participates in fatty acid beta-oxidation upon binding of acyl-L-carnitine. Biochem. Biophys. Res. Commun., 735: 150481.
Fan AL, Zhong BY, Liu D, Lu YB, Wu MY, Jin HW, Shi XM, Ren JW , Zhang B, Su XD, Ma M, Li SM , Lin WH. (2024) Biosynthesis of epipyrone a reveals a highly speciffc membrane bound fungal C‑glycosyltransferase for pyrone galactosylation. Org. Lett., 26: 1160-1165.
Zhang Y, Xu YP, Nie JK, Chen H, Qin G, Wang B, Su XD. (2023) DNA–TCP complex structures reveal a unique recognition mechanism for TCP transcription factor families. Nucl. Acids Res., 51: 434-448.
Wang B, Xu H, Liang ZT, Zhao TN, Zhang X, Peng TB, Wang YC, Su XD. (2023) Human antibody BD-218 has broad neutralizing activity against concerning variants of SARS-CoV-2. Int. J Biol. Macromol., 227: 896-902.
Chen CT, Song XH, Yu YL, Wang XW, Xu H, Ji WW, Ma JC, Zhao CY, Feng SL, Wang YC, Su XD, Wang W. (2023) Aptamer-based nanointerferometer enables amplification-free ultrasensitive detection and differentiation of SARS-CoV-2 variants. Anal. Chim. Acta, 1260: 341207.
Feng SL, Yu YL, Ma JC, Wang XW, Song XH, Xu H, Li YB, Mo KJ, Liu P, Song X, Xie ZL, Wang YC, Su XD, Wang W, Chen CT. (2023) High-affinity aptamers enable the rapid optical detection and differentiation of three SARS-CoV-2 VOCs. Microchem. J., 195: 109508.
Zhang LG, Ma J, Shen ZR, Wang B, Jiang QL, Ma F, Ju Y, Duan GX, Zhang Q, Su XD, Sodmergen.(2023) Low copy numbers for mitochondrial DNA moderates the strength of nuclear-cytoplasmic incompatibility in plants. J. Integr. Plant Biol., 65: 739-754.
Chen H, Xu YP, Jin JS, Su XD. (2023) KaScape: a sequencing-based method for global characterization of protein‒DNA binding affinity. Sci. Rep., 13: 16595.
Cheng Y, Wang HB, Xu H, Liu Y, Ma B, Chen XM, Zeng X, Wang XG, Wang B, Shiau C, Ovchinnikov S, Su XD, Wang C. (2023) Co-evolution-based prediction of metal-binding sites in proteomes by machine learning. Nat. Chem. Biol., 19: 548-555.
Falco AD, Caruso F, Su XD, Iavarone A, Ceccarelli M. (2023) A variational algorithm to detect the clonal copy number substructure of tumors from scRNA-seq data. Nat. Commun., 14: 1074.
Feng J , Zhao Z, Wei YF, Bao ZS , Zhang W, Wu F, Li GZ , Sun ZY , Tan YL , Li JY , Zhang YQ ,Duan ZJ , Qi XL , Yu K , Cong ZM , Yang JJ , Wang YX , Sun YY , Tang FC ,Su XD, Fang C, Jiang T, Fan XL. (2023) Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma. Front. Med., 17: 240-262.
Wei YF, Li GZ, Feng J, Wu F, Zhao Z, Bao ZS, Zhang W, Su XD, Li JY, Qi XL, Duan ZJ, Zhang YQ, Vega SF, Jakola AS, Sun YY, Carén H, Jiang T, Fan XL. (2023) Stalled oligodendrocyte differentiation in IDH-mutant gliomas. Genome Biol.,15: 24.
Li F, Yang JJ, Sun ZY, Wang L, Qi LY, A S, Liu YQ, Zhang HM, Dang LF, Wang SJ, Luo CX , Nian WF, O’Connerg S, Ju LZ, Quan WP, Li XK, Wang C, Wang DP, You HL, Cheng ZK, Yan J, Tang FC, Yang DC, Xia CW, Gao G, Wang Y, Zhang BC, Zhou YH, Guo X, Xiang SH, Liu H, Peng TB, Su XD, Chen Y, Ouyang Q, Wang DH , Zhang DM, Xu ZH, Hou HW, Bai SN , Li L. (2023) Plant-on-chip: Core morphogenesis processes in the tiny plant Wolffia australiana. PNAS Nexus, 2: 1-18.
Zhang JW, Wang JL, Li MX, Su XD, Tian YF, Wang PW, Zhou XZ, Jin GS, Liu FS. (2023) Oncolytic HSV-1 suppresses cell invasion through downregulating Sp1 in experimental glioblastoma. Cell Signal., 103: 110581.
Lupala CS, Ye YJ, Chen H, Su XD, Liu HG. (2022) Mutations on RBD of SARS-CoV-2 Omicron variant result in stronger binding to human ACE2 receptor. Biochem. Biophys. Res. Commun., 590: 34-41.
Hei Y, Chen Y, Li Q, Mei Z, Pan JJ, Zhang SQ, Xiong CY, Su XD, Wei SC. (2022) Multifunctional immunoliposomes enhance the immunotherapeutic effects of PD-L1 antibodies against melanoma by reprogramming immunosuppressive tumor microenvironment. Small, 18: e2105118.
Zhang SQ, Sui Y, Yan S, Zhang YF, Ding C, Su XD, Xiong JW, Wei SC. (2022) Retinoic acid and FGF10 promote the differentiation of pluripotent stem cells into salivary gland placodes. Stem Cell Res. Ther., 13: 368.
Zheng XB, Song JN, Yu CN, Zhou ZG, Liu XW, Yu J, Xu GC, Yang JQ, He XJ, Bai X, Luo Y, Bao Y, Li HF, Yang L, Xu MQ, Song N, Su XD, Xu J, Ma XL Shi HB. (2022) Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis. Signal Transduct. Target. Ther., 7: 60.
Lupala CS, Kumar V, Su XD, Wu C, Liu HG. (2022) Computational insights into differential interaction of mammalian angiotensin-converting enzyme 2 with the SARS-CoV-2 spike receptor binding domain. Comput. Biol. Med., 141: 105017.
Wang MY, Zhang L, Li QQ, Wang B, Liang ZY, Sun YQ, Nie JH, Wu JJ, Su XD, Qu XW, Li YH, Wang YC, Huang WJ. (2022) Reduced sensitivity of the SARS-CoV-2 Lambda variant to monoclonal antibodies and neutralizing antibodies induced by infection and vaccination. Emerg.Microbes Infect., 11: 18-29.
Tabar MS, Parsania C, Chen H, Su XD, Bailey CG, Rasko JEJ. (2022) Illuminating the dark protein-protein interactome. Cell Rep. Methods., 2: 100275.
Xu H, Wang B, Zhao TN, Liang ZT, Peng TB, Song XH, Wu JJ, Wang YC, Su XD. (2021) Structure-based analyses of neutralization antibodies interacting with naturally occurring SARS-CoV-2 RBD variants. Cell Res., 31: 1126–1129.
Liu WZ, Li J, Xu YP, Yin DB, Zhu X, Fu HY, Su XD, Guo XF. (2021) Complete Mapping of DNA-Protein Interactions at the Single-Molecule Level. Adv. Sci., 8: e2101383.
Dai LQ, Xu YP, Du ZW, Su XD, Yu J. (2021) Revealing atomic-scale molecular diffusion of a plant-transcription factor WRKY domain protein along DNA. Proc. Natl. Acad. Sci. U. S. A., 118: e2102621118.
Lupala CS, Li XX, Lei J, Chen H, Qi JX, Liu HG, Su XD. (2021) Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein. Quant. Biol., 9: 61-72.
Zhang L, Cui ZM, Li QQ, Wang B, Yu YL, Wu JJ, Nie JH, Ding RX, Wang HX, Zhang Y, Liu S, Chen ZH, He YQ, Su XD, Xu WB, Huang WJ , Wang YC. (2021) Ten emerging SARS-CoV-2 spike variants exhibit variable infectivity, animal tropism, and antibody neutralization. Commu. Biol., 4: 1196.
Garofano L, Migliozzi S, Oh YT, D’Angelo F, Najac RD, Ko A, Frangaj B, Caruso FP, Yu K, Yuan J, Zhao W, Di Stefano AL, Bielle F, Jiang T, Sims P, Suvà ML, Tang F,Su XD, Ceccarelli M, Sanson M, Lasorella A, Lavarone A. (2021) Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat. Cancer., 2: 141-156.
Lupala CS, Kumar V,Su XD, Wu C, Liu HG. (2021) Computational insights into differential interaction of mammalian angiotensin-converting enzyme 2 with the SARS-CoV-2 spike receptor binding domain. Comput. Biol. Med., 105017.
Du S, Cao YL, Zhu QY, Yu P, Qi FF, Wang GP, Du XX, Bao LL, Deng W, Zhu H, Liu JN, Nie JH, Zheng YH, Liang HY, Liu RX, Gong SR, Xu H, Yisimayi AJ, Lv Q, Wang B, He RS, Han YL, Zhao WJ, Bai YL, Qu YJ, Gao X, Ji CG, Wang QS, Gao N, Huang WJ, Wang YC, Xie XS,S u XD, Xiao JY, Qin C. (2020) Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy. Cell, 183: 1013-1023.
Li YX, Wang GP, Li NN, Wang YX, Zhu QY, Chu HR, Wu WJ, Tan Y, Yu F, Su XD, Gao N, Xiao JY. (2020) Structural insights into immunoglobulin M. Science, 367: 1014-1017.
Xu YP, Xu H, Wang B, Su XD. (2020) Crystal structures of N-terminal WRKY transcription factors and DNA complexes. Protein Cell., 11: 208-213.
Yu K, Hu YQ, Wu F, Guo QF, Qian ZH, Hu WE, Chen J, Wang KY, Fan XY, Wu XL, Rasko JEJ, Fan XL, Iavarone A, Jiang T, Tang FC, Su XD. (2020) Surveying brain tumor heterogeneity by single-cell RNA-sequencing of multi-sector biopsies. Natl. Sci. Rev., 7: 1306-1318.
Ye ZY, Brostromer E, Nan J, Cao XF, Liu X, Qiao L, Liu ZJ,Su XD. (2020) Protein crystallization benefits from the rough well surface of a 48-well polystyrene microplate.J. Cryst. Growth, 532: 125425.
Zhao Z, Ma ZX, Wang B, Guan YK, Su XD, Jiang ZF. (2020) Mn2+directly activates cGAS and structural analysis suggests Mn2+induces a noncanonical catalytic synthesis of 2'3'-cGAMP.Cell Rep., 32: 108053.
Cao YL, Su B, Guo XH, Sun WJ, Deng YQ, Bao LL, Zhu QY, Zhang X, Zheng YH, Geng CY, Chai XR, He RS, Li XF, Lv Q, Zhu H, Deng W, Xu YF, Wang YJ, Qiao LX, Tan YF, Song LY, Wang GP, Du XX, Gao N, Liu JN, Xiao JY, Su XD, Du ZM, Feng YM, Qin C, Qin CF, Jin RH, Xie XS. (2020) Potent neutralizing antibodies against SARS-CoV-2 Identified by high-throughput single-cell sequencing of convalescent patients' B cells. Cell, 182: 73-84.
Zhao K, Li YW, Liu ZY, Long HF, Zhao CY, Luo F, Sun YP, Tao YQ, Su XD, Li D, Li XM, Liu C. (2020) Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Nat. Commun., 11: 2643.
Sun YP, Hou SQ, Zhao K, Long HF, Liu ZY, Gao J, Zhang YY, Su XD, Li D, Liu C. (2020) Cryo-EM structure of full-length α-synuclein amyloid fibril with Parkinson’s disease familial A53T mutation. Cell Res., 30: 360-362.
Caruso FP, Garofano L, D'Angelo F, Yu K, Tang FC, Yuan JZ, Zhang J, Cerulo LG, Pagnotta SM, Bedognetti D, Sims PA, SuvàM, Su XD, Lasorella A, Lavarone A, Ceccarelli M. (2020) A map of tumor–host interactions in glioma at single-cell resolution. GigaScience, 9: 1-14.
于佳慧、徐华、陈红、赵天宁、彭天博、宋晓慧、陈楚昕、黄彬尧、杨天怡、陈星禹、林影、董朔含、王安祺、袁闯、陈睿琦
