8U4S

Structure of trimeric CXCR4 in complex with REGN7663 Fab

8U4S の概要

• エントリーDOI: 10.2210/pdb8u4s/pdb
• EMDBエントリー: 41888 41889 41890 41891 41892 41893 41894
• 分子名称: REGN7663 Fab light chain, REGN7663 Fab heavy chain, C-X-C chemokine receptor type 4, ... (5 entities in total)
• 機能のキーワード: gpcr, chemokine receptor, trimer, oligomer, antibody, signaling protein-immune system complex, signaling protein/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 367493.05

構造登録者

Saotome, K.,McGoldrick, L.L.,Franklin, M.C. (登録日: 2023-09-11, 公開日: 2024-03-13, 最終更新日: 2025-02-26)

主引用文献

Saotome, K.,McGoldrick, L.L.,Ho, J.H.,Ramlall, T.F.,Shah, S.,Moore, M.J.,Kim, J.H.,Leidich, R.,Olson, W.C.,Franklin, M.C.
Structural insights into CXCR4 modulation and oligomerization.
Nat.Struct.Mol.Biol., 32:315-325, 2025

PubMed Abstract: Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.

PubMed: 39313635
DOI: 10.1038/s41594-024-01397-1

実験手法

ELECTRON MICROSCOPY (3.35 Å)