Crystal Structures of CXCR4 complexed to CXCL12

CXCR4 与 CXCL12 复合的晶体结构

基本信息

批准号：
8143383
负责人：
ELIAS LOLIS
金额：
$ 20.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-16 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143383
关键词：
AMD3100 Adenosine A2A Receptor Adrenergic Agents Adrenergic Receptor Adult Agonist Back Binding C-terminal CD34 gene CXC Chemokines CXCL12 gene CXCR4 gene Cattle Cells Collaborations Complex Crystallization Data Dimerization Disaccharides Disease Drug Delivery Systems Embryonic Development FDA approved Family Fetus Foundations Future G-Protein-Coupled Receptors Germ Cells Glycosaminoglycans Goals Growth HIV Envelope Protein gp120 HIV-1 Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hereditary Disease Herpesviridae Homeostasis Human Illusions Immigration Immunosuppression Immunosuppressive Agents Institutes Laboratories Letters Ligands Location Malignant Neoplasms Medical Membrane Multiple Myeloma Mutate Mutation Neoplasm Metastasis Non-Hodgkin&apos s Lymphoma Pathology Peripheral Pharmaceutical Preparations Phase Physiological Pichia Positioning Attribute Process Protein Binding Proteins Publishing Recombinants Resolution Retina Rhodopsin Robot Roentgen Rays Role Route Sampling Signal Transduction Solid Solutions Specificity Staging Stress Stromal Cell-Derived Factor 1 Structure Syndrome Testing Toothpaste Universities Viral Work X-Ray Crystallography adrenergic base beta-Chemokines cell motility chemokine chemokine receptor design dimer heparin disaccharide milligram monomer mutant public health relevance receptor response retinal rods small molecule therapeutic vaccine three dimensional structure vMIP-II

项目摘要

DESCRIPTION (provided by applicant): CXCR4 is a G-protein coupled receptor is activated by a sole physiological agonist, the chemokine CXCL12 and functions to cause the migration of cells to the appropriate anatomical location during embryonic development and in response to stress in adults. CXCR4 is also involved in growth and/or metastasis of a number of cancers, is a co-receptor for HIV-1, and mutant CXCR4 causes an immunosuppressive condition known as WHIM syndrome. A chemokine released by herpesvirus-8, v-MIP-II, is an antagonist of CXCR4. CXCL12 and vCCL2 belong to different subfamilies of the chemokine family as defined by their sequence and structure, and would be expected to expected to activate receptors within their subfamily. This proposal aims to determine the three-dimensional structures of the structures of CXCR4 complexed to (a) mutated CXCL12P2G that functions as an antagonist and (b) CXCL12P2G in the context of another mutation (H25R), which is predominantly a monomer in solution. Glycosaminoglycans are known to interact with most chemokines and promote the formation of dimers and oligomerization. Crystallization in the presence and absence of a heparin disaccharide known to bind CXCL12 at two locations (determined by X-ray crystallography in the PI's lab) and to promote dimerization will also be performed to test the hypothesis that glycosaminoglycans present chemokines to their receptors. These structures will be compared to each other and the CXCR4-AMD3100 (a small molecule antagonist) complex, a complex which has been crystallized by the collaborator (Dr. Ray Steven's, Scripps Institute) and its high resolution structure is in progress. Structural work with CXCR4 will lay the foundation for future work involving endogenous and HIV-1 proteins that bind CXCR4 and have medical relevance. PUBLIC HEALTH RELEVANCE: The chemokine receptor CXCR4 is a G-protein coupled receptor involved in HIV-1 entry, the metastasis and growth of several cancers and, when mutated at the C-terminus, responsible for the immunosuppressive disorder known as WHIM syndrome. It is also the target of the drug, Plexifor, for CD34+ peripheral cell mobilization used for multiple myeloma and non-Hodgkin's lymphoma. This proposal seeks to determine the three-dimensional structure of CXCL12 complexed to CXCR4.

描述（由申请人提供）：CXCR4 是一种 G 蛋白偶联受体，由唯一的生理激动剂趋化因子 CXCL12 激活，其功能是在胚胎发育过程中引起细胞迁移到适当的解剖位置，并响应成人的应激。 CXCR4 还参与多种癌症的生长和/或转移，是 HIV-1 的共同受体，突变的 CXCR4 会导致称为 WHIM 综合征的免疫抑制病症。疱疹病毒 8 释放的趋化因子 v-MIP-II 是 CXCR4 的拮抗剂。根据其序列和结构定义，CXCL12 和 vCCL2 属于趋化因子家族的不同亚家族，并且预计会激活其亚家族内的受体。该提案旨在确定 CXCR4 与 (a) 充当拮抗剂的突变 CXCL12P2G 和 (b) 另一个突变 (H25R) 背景下的 CXCL12P2G（主要是溶液中的单体）复合的 CXCR4 结构的三维结构。已知糖胺聚糖与大多数趋化因子相互作用并促进二聚体和寡聚化的形成。还将在存在和不存在已知在两个位置结合 CXCL12 的肝素二糖（通过 PI 实验室的 X 射线晶体学测定）并促进二聚化的情况下进行结晶，以测试糖胺聚糖向其受体呈递趋化因子的假设。这些结构将相互比较，并与 CXCR4-AMD3100（一种小分子拮抗剂）复合物进行比较，该复合物已由合作者（Scripps 研究所的 Ray Steven 博士）结晶，其高分辨率结构正在进行中。 CXCR4 的结构工作将为未来涉及结合 CXCR4 并具有医学相关性的内源性和 HIV-1 蛋白的工作奠定基础。公共健康相关性：趋化因子受体 CXCR4 是一种 G 蛋白偶联受体，参与 HIV-1 的进入、多种癌症的转移和生长，并且当 C 末端突变时，会导致称为 WHIM 综合征的免疫抑制疾病。它也是药物 Plexifor 的靶标，用于动员 CD34+ 外周细胞，用于治疗多发性骨髓瘤和非霍奇金淋巴瘤。该提案旨在确定 CXCL12 与 CXCR4 复合的三维结构。