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

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

Author information

1
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397 Biberach, Germany.
2
LeadXpro AG, PARK InnovAARE, 5234 Villigen, Switzerland.
3
Swiss Light Source, Paul Scherrer Institute, 5232 Villigen, Switzerland.
4
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397 Biberach, Germany. Electronic address: gisela.schnapp@boehringer-ingelheim.com.

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 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

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

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