Crystal Structures of CXCR4 complexed to CXCL12

CXCR4 与 CXCL12 复合的晶体结构

• 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
• 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' 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

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）：CXCR 4是一种G蛋白偶联受体，由唯一的生理激动剂趋化因子CXCL 12激活，并在胚胎发育过程中和成年人对应激的反应中起引起细胞迁移到适当解剖位置的作用。CXCR 4还参与许多癌症的生长和/或转移，是HIV-1的共受体，并且突变的CXCR 4引起称为WHIM综合征的免疫抑制病症。由疱疹病毒-8释放的趋化因子v-MIP-II是CXCR 4的拮抗剂。CXCL 12和vCCL 2属于由其序列和结构定义的趋化因子家族的不同亚家族，并且预期将预期激活其亚家族内的受体。该提议旨在确定CXCR 4的结构的三维结构，所述CXCR 4与（a）作为拮抗剂起作用的突变的CXCL 12 P2 G和（B）在另一突变（H25 R）的情况下的CXCL 12 P2 G复合，所述突变（H25 R）在溶液中主要是单体。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CXCL 12（在PI实验室中通过X射线晶体学测定）并促进二聚化的肝素二糖的情况下进行结晶，以检验糖胺聚糖将趋化因子呈递给其受体的假设。这些结构将相互比较，CXCR 4-AMD 3100（一种小分子拮抗剂）复合物，一种由合作者（Ray Steven博士，Scripps研究所）结晶的复合物，其高分辨率结构正在进行中。CXCR 4的结构工作将为未来涉及结合CXCR 4并具有医学相关性的内源性和HIV-1蛋白的工作奠定基础。 公共卫生相关性：趋化因子受体CXCR 4是一种G蛋白偶联受体，参与HIV-1进入、转移和几种癌症的生长，并且当在C末端突变时，负责称为WHIM综合征的免疫抑制性疾病。它也是药物Plexifor的靶点，用于多发性骨髓瘤和非霍奇金淋巴瘤的CD 34+外周细胞动员。该提案旨在确定与CXCR 4复合的CXCL 12的三维结构。