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PDBsum entry 6gps
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Signaling protein
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PDB id
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6gps
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References listed in PDB file
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Key reference
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Title
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Crystal structure of cc chemokine receptor 2a in complex with an orthosteric antagonist provides insights for the design of selective antagonists.
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Authors
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A.K.Apel,
R.K.Y.Cheng,
C.S.Tautermann,
M.Brauchle,
C.Y.Huang,
A.Pautsch,
M.Hennig,
H.Nar,
G.Schnapp.
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Ref.
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Structure, 2019,
27,
427.
[DOI no: ]
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PubMed id
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Abstract
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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.
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