6GPS

CRYSTAL STRUCTURE OF CCR2A IN COMPLEX WITH MK-0812

Summary for 6GPS

• Entry DOI: 10.2210/pdb6gps/pdb
• Related: 5t1a
• Descriptor: C-C chemokine receptor type 2,Rubredoxin,C-C chemokine receptor type 2, ZINC ION, [(3~{S},4~{S})-3-methoxyoxan-4-yl]-[(1~{R},3~{S})-3-propan-2-yl-3-[[3-(trifluoromethyl)-7,8-dihydro-5~{H}-1,6-naphthyridin-6-yl]carbonyl]cyclopentyl]azanium (3 entities in total)
• Functional Keywords: gpcr, signalling, drug-design, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 48814.14

Authors

Pautsch, A.,Schnapp, G. (deposition date: 2018-06-07, release date: 2019-01-02, Last modification date: 2019-03-13)

Primary citation

Apel, A.K.,Cheng, R.K.Y.,Tautermann, C.S.,Brauchle, M.,Huang, C.Y.,Pautsch, A.,Hennig, M.,Nar, H.,Schnapp, G.
Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists.
Structure, 27:427-438.e5, 2019

PubMed Abstract: 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 E291 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 H121, 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.

PubMed: 30581043
DOI: 10.1016/j.str.2018.10.027

Experimental method

X-RAY DIFFRACTION (3.3 Å)