变构调节
调制(音乐)
CXCR4型
变构调节剂
领域(数学分析)
化学
受体
细胞生物学
生物物理学
生物
生物化学
物理
数学
趋化因子
声学
数学分析
作者
Eva M. García‐Cuesta,Pablo Martínez,Karthik Selvaraju,Adrián Miguel Gómez Pozo,Gianluca D’Agostino,Sofía Gardeta,Adriana Quijada‐Freire,Patricia Blanco Gabella,Carlos Roca,Rodrigo Jiménez‐Saiz,Alfonso García‐Rubia,Blanca Soler-Palacios,Pilar Lucas,Rosa Ayala-Bueno,Noelia Santander Acerete,Yolanda R. Carrasco,Ana Martı́nez,Nuria E. Campillo,Lasse D. Jensen,José Miguel Rodríguez‐Frade,César Santiago,Mario Mellado
摘要
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.
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