Crystal Structures of CXCR4 complexed to CXCL12

CXCR4 与 CXCL12 复合的晶体结构

• 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
• 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' 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

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(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，功能是在胚胎发育期间导致细胞迁移到适当的解剖位置，并对成年患者的压力做出反应。CXCR4还参与了许多癌症的生长和/或转移，是HIV-1的共同受体，突变的CXCR4会导致一种称为突发综合征的免疫抑制情况。疱疹病毒8型释放的趋化因子v-MIP-II是CXCR4的拮抗剂。根据其序列和结构，CXCL12和vCCL2属于趋化因子家族中不同的亚家族，有望激活其亚家族内的受体。本建议旨在确定CXCR4与(A)作为拮抗剂的突变的CXCL12P2G和(B)在另一突变(H25R)的背景下形成的CXCL12P2G的复合结构的三维结构，该突变主要是溶液中的单体。已知糖胺多糖与大多数趋化因子相互作用，并促进二聚体的形成和寡聚。在有或没有肝素二糖存在和不存在的情况下，也将进行结晶，以验证糖胺聚糖向其受体递送趋化因子的假设。肝素二糖可在两个位置与CXCL12结合(由PI实验室的X射线结晶学确定)并促进二聚化。这些结构将相互比较，并与CXCR4-AMD3100(一种小分子拮抗剂)复合体进行比较，CXCR4-AMD3100复合体已由合作者(斯克里普斯研究所的Ray Steven博士)结晶，其高分辨结构正在进行中。CXCR4的结构工作将为未来涉及内源性和HIV-1蛋白的工作奠定基础，这些蛋白结合CXCR4并具有医学意义。 公共卫生相关性：趋化因子受体CXCR4是一种G蛋白偶联受体，参与HIV-1的进入，几种癌症的转移和生长，当C末端突变时，导致被称为突发综合征的免疫抑制障碍。它也是药物Plexifor的靶点，用于CD34+外周细胞动员，用于多发性骨髓瘤和非霍奇金淋巴瘤。这一建议旨在确定与CXCR4络合的CXCL12的三维结构。