2. Academic Validation
  3. Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists

Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists

  • Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2425795122. doi: 10.1073/pnas.2425795122.
Xiaohong Sang # 1,  Haizhan Jiao # 2,  Qian Meng 3,  Xiong Fang 3,  Qi Pan 2,  Jiao Zhou 1,  Tingli Qian 1,  Wanqin Zhang 2,  Yan Xu 4,  Jing An 4,  Ziwei Huang 1 3 4,  Hongli Hu 2
Affiliations

Affiliations

  • 1 Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
  • 2 Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
  • 3 School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA 92037.
  • # Contributed equally.
PMID: 40063796 DOI: 10.1073/pnas.2425795122
Abstract

CXCR4 (CXC Chemokine Receptor type 4), a member of the G protein-coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics targeting CXCR4 have been under intensive investigation. To date, only two small-molecule antagonist drugs targeting CXCR4, plerixafor (AMD3100) and mavorixafor (AMD070), have been approved. Here, we present the high-resolution structures of CXCR4 complexed with AMD3100 and AMD070, as well as a small-molecule antagonist HF51116 that has very different chemical structure and binding mechanism from AMD3100 and AMD070. The interactions between these antagonists and the receptor are analyzed in details, and the mechanisms of antagonism are elucidated. Both the major and minor subpockets on CXCR4 are found to be involved in binding of these small-molecule antagonists. The distinct conformations of Trp942.60 observed in these structures highlight the plasticity of the binding pocket on CXCR4, offering valuable insights into the exploration and refinement of therapeutic strategies targeting this Chemokine Receptor.

Keywords

CXCR4; G-protein coupled receptor; chemokine receptor; cryo-EM structure; small molecule antagonist.

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