8U4O

Structure of CXCL12-bound CXCR4/Gi complex

Summary for 8U4O

• Entry DOI: 10.2210/pdb8u4o/pdb
• EMDB information: 41888 41889 41890 41891 41892 41893 41894
• Descriptor: C-X-C chemokine receptor type 4, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, chemokine receptor, chemokine, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 167415.24

Authors

Saotome, K.,McGoldrick, L.L.,Franklin, M.C. (deposition date: 2023-09-11, release date: 2024-03-13, Last modification date: 2024-10-30)

Primary citation

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., 2024

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

Experimental method

ELECTRON MICROSCOPY (3.29 Å)