Atoms-to-Animals: Structural Genomics of Immunity

原子到动物：免疫结构基因组学

• 批准号: 9266109
• 负责人: Arturo Casadevall
• 金额: $ 48.07万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266109
• 关键词: Atoms; Animals; Structural; Genomics; Immunity

DESCRIPTION (provided by applicant): The Immune Function Network (IFN), a consortium of immunologists, geneticists, computational biochemists, and high throughput structural biologists, is committed to the coordinated structural, in vitro biochemical and in vivo functional analyses of the secreted molecules and ectodomains of cell surface molecules that control adaptive and innate immunity. These molecules are validated targets for immune-based therapies to treat a wide range of autoimmune diseases, infectious diseases and cancers, and are indeed therapeutics in their own right. The IFN, subscribes to a series of underlying principles: 1) target selection supports hypothesis-driven structural biology by identifying unique primary amino acid sequence signatures that predict unique structural features, which are in turn responsible for unique biological function; 2) the high resolution structures of these molecules are exceptionally revealing as they inform on oligomeric state, valency, specificity and general architectural features, all of which are fundamental mechanistic contributors to immune function; 3) these structures can be readily exploited by biochemical and computational approaches to guide the generation of molecules with specifically altered biochemical and biophysical properties; 4) these "surgically-defined" mutants represent novel reagents that will lead to new mechanistic insights in in vitro cell-based assays and in vivo animal models of disease; 5) the molecules predicted to be most informative will guide the generation of knock-in mouse models to provide in vivo structure-function relationships for innate and adaptive immunity. This "Atoms-to-Animals" approach represents the next step in the evolution of Structural Biology as it maximally leverages structural information and provides a comprehensive and powerful paradigm for the study of normal, pathological, and therapeutic immune responses.

描述（由申请人提供）：免疫功能网络（IFN）是一个由免疫学家、遗传学家、计算生物化学家和高通量结构生物学家组成的联盟，致力于对控制适应性和先天性免疫的细胞表面分子的分泌分子和胞外域进行协调的结构、体外生物化学和体内功能分析。这些分子是基于免疫的疗法的经验证的靶标，用于治疗广泛的自身免疫性疾病、感染性疾病和癌症，并且确实是其本身的治疗剂。IFN遵循一系列基本原则：1）靶选择通过鉴定预测独特结构特征的独特一级氨基酸序列特征来支持假说驱动的结构生物学，所述独特一级氨基酸序列特征进而负责独特的生物学功能; 2）这些分子的高分辨率结构特别具有启示性，因为它们提供了寡聚状态、化合价、特异性和一般结构特征，所有这些都是免疫功能的基本机制贡献者; 3）这些结构可以很容易地被生物化学和计算利用， 4）这些“化学定义的”突变体代表了新的试剂，其将导致在体外基于细胞的测定和体内疾病动物模型中的新的机理见解; 5）被预测为最具信息性的分子将指导基因敲入小鼠模型的产生以提供体内结构-先天免疫和适应性免疫的功能关系。这种“原子到动物”的方法代表了结构生物学进化的下一步，因为它最大限度地利用了结构信息，并为正常，病理和治疗性免疫反应的研究提供了全面而强大的范例。

项目成果

Modularity of Protein Folds as a Tool for Template-Free Modeling of Structures.

• DOI: 10.1371/journal.pcbi.1004419
• 发表时间: 2015-08
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Vallat B;Madrid-Aliste C;Fiser A
• 通讯作者: Fiser A

Functional clustering of immunoglobulin superfamily proteins with protein-protein interaction information calibrated hidden Markov model sequence profiles.

• DOI: 10.1016/j.jmb.2013.11.009
• 发表时间: 2014-02-20
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Yap, Eng-Hui;Rosche, Tyler;Almo, Steve;Fiser, Andras
• 通讯作者: Fiser, Andras

Computational design of a synthetic PD-1 agonist.

• DOI: 10.1073/pnas.2102164118
• 发表时间: 2021-07-20
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bryan CM;Rocklin GJ;Bick MJ;Ford A;Majri-Morrison S;Kroll AV;Miller CJ;Carter L;Goreshnik I;Kang A;DiMaio F;Tarbell KV;Baker D
• 通讯作者: Baker D

Functional classification of immune regulatory proteins.

• DOI: 10.1016/j.str.2013.02.022
• 发表时间: 2013-05-07
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Rubinstein, Rotem;Ramagopal, Udupi A.;Nathenson, Stanley G.;Almo, Steven C.;Fiser, Andras
• 通讯作者: Fiser, Andras