Structural basis for ligand modulation of the CCR2 conformational landscape.

Structural basis for ligand modulation of the CCR2 conformational landscape.

Publication date: Apr 11, 2019

CC chemokine receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands, named for the adjacent cysteine motif on their N terminus. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. CCR2, in particular, promotes the metastasis of cancer cells and is also implicated in autoimmunity-driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long-timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation and disrupt a continuous internal water and sodium ion pathway, preventing transitions to an active-like state. Several metastable conformations present a cryptic drug-binding pocket near the allosteric site that may be amenable to targeting with small molecules. Without antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2 and may also be useful for future drug design.

Taylor, B.C., Lee, C.T., and Amaro, R.E. Structural basis for ligand modulation of the CCR2 conformational landscape. 17741. 2019 Proc Natl Acad Sci U S A.

Concepts Keywords
Allosteric Drug design
Antagonist Receptor antagonist
Asthma Allosteric regulation
Atherosclerosis G protein-coupled receptor
Autoimmunity Chemokine
Basal CCR2
Chemokine Integral membrane proteins
Chemokine Receptor Cytokines
Conformation Cell signaling
Coupling Cell biology
Crystal Signal transduction
Cysteine Branches of biology
Diabetic Nephropathy Rheumatoid arthritis
Drug Design Range diseases
Endogenous Metastasis
G Protein
Ion
Ligand
Ligands
Metastable
Metastasis
Modulation
Molecular Dynamics
Motif
Multiple Sclerosis
Neuropathic Pain
Receptors
Rheumatoid Arthritis
Sci
Sodium
Type 1 Diabetes

Semantics

Type Source Name
gene UNIPROT FZD4
gene UNIPROT LPAR3
gene UNIPROT MRGPRX3
gene UNIPROT GPR151
gene UNIPROT MRGPRX4
gene UNIPROT OXER1
gene UNIPROT GPRC6A
gene UNIPROT LGR6
gene UNIPROT MRGPRX1
gene UNIPROT AOPEP
gene UNIPROT CFC1
drug DRUGBANK Water
pathway BSID Rheumatoid arthritis
disease DOID rheumatoid arthritis
disease MESH rheumatoid arthritis
disease MESH neuropathic pain
disease DOID atherosclerosis
disease MESH atherosclerosis
pathway BSID Asthma
disease DOID asthma
disease MESH asthma
disease DOID multiple sclerosis
disease MESH multiple sclerosis
disease MESH diabetic nephropathy
disease MESH autoimmunity
disease DOID cancer
disease MESH cancer
disease MESH metastasis
drug DRUGBANK L-Cysteine
gene UNIPROT CCR2

Original Article

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