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A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C axe weak partial agonists
文献类型：期刊论文
| 作者 | Zhang, WB; Navenot, JM; Haribabu, B; Tamamura, H; Hiramatu, K; Omagari, A; Pei, G; Manfredi, JP; Fujii, N; Broach, JR |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2002 |
| 卷号 | 277期号:27页码:24515-24521 |
| 通讯作者 | Peiper, SC (reprint author), Univ Louisville, Henry Vogt Canc Res Inst, Louisville, KY 40202 USA., |
| 英文摘要 | CXCR4 is a G protein-coupled receptor for stromal-derived factor 1 (SDF-1) that plays a critical role in leukocyte trafficking, metastasis of mammary carcinoma, and human immunodeficiency virus type-1 infection. To elucidate the mechanism for CXCR4 activation, a constitutively active mutant (CAM) was derived by coupling the receptor to the pheromone response pathway in yeast. Conversion of Asn-119 to Ser or Ala, but not Asp or Lys, conferred autonomous CXCR4 signaling in yeast and mammalian cells. SDF-1 induced signaling in variants with substitution of Asn-119 to Ser, Ala, or Asp, but not Lys. These variants had similar cell surface expression and binding affinity for SDF-1. CXCR4-CAMs were constitutively phosphorylated and present in cytosolic inclusions. Analysis of antagonists revealed that exposure to AAM3100 or ALX40-4C induced G protein activation by CXCR4 wild type, which was greater in the CAM, whereas T140 decreased autonomous signaling. The affinity of AAM3100 and ALX40-4C binding to CAMs was less than to wild type, providing evidence of a conformational shift. These results illustrate the importance of transmembrane helix 3 in CXCR4 signaling. Insight into the mechanism for CXCR4 antagonists will allow for the development of a new generation of agents that lack partial agonist activity that may induce toxicities, as observed for AMD3100. |
| 学科主题 | Biochemistry & Molecular Biology |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | PROTEIN-COUPLED RECEPTOR ; HUMAN-IMMUNODEFICIENCY-VIRUS ; CHEMOKINE RECEPTOR ; KAPOSIS-SARCOMA ; LYMPHOCYTE CHEMOATTRACTANT ; HIV-1 ENTRY ; SDF-1 ; ACTIVATION ; INHIBITOR ; LIGAND |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000176611800072 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/2546]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Zhang, WB,Navenot, JM,Haribabu, B,et al. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C axe weak partial agonists[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2002,277(27):24515-24521. |
| APA | Zhang, WB.,Navenot, JM.,Haribabu, B.,Tamamura, H.,Hiramatu, K.,...&Peiper, SC.(2002).A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C axe weak partial agonists.JOURNAL OF BIOLOGICAL CHEMISTRY,277(27),24515-24521. |
| MLA | Zhang, WB,et al."A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C axe weak partial agonists".JOURNAL OF BIOLOGICAL CHEMISTRY 277.27(2002):24515-24521. |
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