Crystal Structures of CXCR4 complexed to CXCL12

CXCR4 与 CXCL12 复合的晶体结构

基本信息

批准号：
7977990
负责人：
ELIAS LOLIS
金额：
$ 24.83万
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/7977990
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 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G蛋白偶联受体，由唯一的生理激动剂，趋化因子CXCL12激活，并引起细胞在胚胎发育过程中迁移到适当的解剖位置，并响应成人的压力。 CXCR4还参与了许多癌症的生长和/或转移，是HIV-1的共受体，突变体CXCR4会导致免疫抑制疾病，称为WHIM综合征。疱疹病毒8（V-MIP-II）释放的趋化因子是CXCR4的拮抗剂。 CXCL12和VCCL2属于趋化因子家族的不同亚家族，其序列和结构定义，预计预期会在其亚科中激活受体。该建议旨在确定CXCR4结构的三维结构，该结构复合于（a）突变的CXCL12P2G，在另一个突变（H25R）的背景下，该提案起作用的CXCL12P2G，以及（b）CXCL12P2G（H25R），这主要是溶液中的一个单位物。已知糖胺聚糖会与大多数趋化因子相互作用，并促进二聚体和低聚的形成。在存在和不存在已知可以在两个位置结合CXCL12的肝素二糖（通过PI实验室中的X射线晶体学确定）并促进二聚化的肝素二糖的结晶也将进行测试，以检验糖胺聚糖酶对受体的糖胺聚糖呈现的假说。这些结构将相互比较，CXCR4-AMD3100（一种小分子拮抗剂）复合物，该复合物已由合作者（Ray Steven's，Scripps Institute）结晶，并且其高分辨率结构正在进行中。与CXCR4的结构性工作将为涉及结合CXCR4并具有医学相关性的内源性和HIV-1蛋白的未来工作奠定基础。公共卫生相关性：趋化因子受体CXCR4是一种参与HIV-1进入的G蛋白偶联受体，几种癌症的转移和生长，并且在C末端发生突变时，负责被称为WHIM综合征的免疫抑制障碍。它也是用于多发性骨髓瘤和非霍奇金淋巴瘤的CD34+外围细胞动员的药物的靶标。该提案旨在确定与CXCR4复合的CXCL12的三维结构。