Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

Structure. 2019 Mar 5;27(3):427-438.e5. doi: 10.1016/j.str.2018.10.027. Epub 2018 Dec 20.


We determined two crystal structures of the chemokine receptor CCR2A in complex with the orthosteric antagonist MK-0812. Full-length CCR2A, stabilized by rubredoxin and a series of five mutations were resolved at 3.3 Å. An N- and C-terminally truncated CCR2A construct was crystallized in an alternate crystal form, which yielded a 2.7 Å resolution structure using serial synchrotron crystallography. Our structures provide a clear structural explanation for the observed key role of residue E2917.39 in high-affinity binding of several orthosteric CCR2 antagonists. By combining all the structural information collected, we generated models of co-structures for the structurally diverse pyrimidine amide class of CCR2 antagonists. Even though the representative Ex15 overlays well with MK-0812, it also interacts with the non-conserved H1213.33, resulting in a significant selectivity over CCR5. Insights derived from this work will facilitate drug discovery efforts directed toward highly selective CCR2 antagonists with potentially superior efficacy.

Keywords: CCR2; GPCR; IMISX in situ crystallization; MK-0812; chemokine receptor; protein engineering; serial crystallography.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Mutation
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Protein Conformation
  • Protein Stability
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / chemistry*
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Rubredoxins / pharmacology
  • THP-1 Cells


  • CCR2 protein, human
  • Naphthyridines
  • Receptors, CCR2
  • Rubredoxins