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Small Molecule Tools to Image and Understand Sophisticated Protein Function

用于成像和理解复杂蛋白质功能的小分子工具

基本信息

批准号：
9276914
负责人：
Alanna Schepartz
金额：
$ 18.98万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276914
关键词：
Binding Biological Process Biology Cell Line Cell Proliferation Cell membrane Cell surface Cells Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Computing Methodologies Crystallography Down-Regulation Drug resistance EGF gene Ensure Epidermal Growth Factor Receptor Event Extracellular Domain Family Funding Generations Geometry Gray unit of radiation dose Growth Health Human Hydrocarbons Image Knowledge Learning Ligands Link MAP Kinase Gene Magic Malignant Neoplasms Membrane Proteins Oncogenes Peptides Phosphotransferases Property Protein Tyrosine Kinase Proteins Receptor Signaling Reporting Role Signal Transduction Specificity Structure Therapeutic Transforming Growth Factor alpha Transmembrane Domain Tyrosine Kinase Inhibitor Ubiquitination Variant Work Wound Healing cellular engineering design expectation extracellular improved inhibitor/antagonist insight interest malignant breast neoplasm mutant novel protein function receptor research study small molecule tool trafficking tyrosine receptor

项目摘要

DESCRIPTION (provided by applicant): In the previous funding cycle, we developed and applied a chemical biology tool called `bipartite Cys4 display'. Bipartite Cys4 display provides structural information about intact proteins that NMR and crystallography cannot and under conditions where structural dynamics are visible. It operates in cells and on targets, like recepto tyrosine kinases, whose dynamic structure is tied intimately to function. With this tool, we gained critical insights into how one receptor tyrosine kinase, the epidermal growth factor receptor (EGFR), an exceptionally important cancer target, communicates chemical information across the plasma membrane. These insights led to molecules-cell penetrating, hydrocarbon-stapled peptides-that inhibit EGFR, in cells, in a new way, via allostery. We also serendipitously discovered novel, allosteric EGFR activators. We learned that growth factor binding to EGFR on the cell surface induces growth factor-dependent coiled coils in the cytoplasmic juxtamembrane segment (JM) that are linked to kinase activation. In this renewal, we first apply state-of-the art structural and computational methods to improve potency and selectivity for activated and drug-resistant (L858R/T790M) EGFR and elucidate the mechanism of EGFR activators for wound healing applications. We build on our discovery that WT, activated, and L858R/T790M EGFR (DM EGFR) differ in a previously unrecognized way- their JM segments contain different coiled coils. This difference provides a path towards molecules that selectively inhibit DM EGFR, alone or synergistically in combination with small molecule tyrosine kinase inhibitors. Next, we interrogate how EGFR decodes JM structure into ligand-dependent biology, and finally broaden our focus to include the heterodimeric ErbB2/3, of great current interest in breast cancer. This work will provide fundamental information on one of the most elusive of all protein functions-allostery-in the context of one of most important human oncogene family-EGFR. We will learn how allostery encodes chemical and mutational information in ErbB proteins, how this information is transmitted into biologic function, and how knowledge of allosteric transitions can guide the design of potent, selective inhibitors (or inhibitor combinations) with novel and needed activities.