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PDBsum entry 4z9g
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Signaling protein
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PDB id
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4z9g
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References listed in PDB file
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Key reference
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Title
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Decoding corticotropin-Releasing factor receptor type 1 crystal structures.
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Authors
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A.S.Dore,
A.Bortolato,
K.Hollenstein,
R.K.Y.Cheng,
R.J.Read,
F.H.Marshall.
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Ref.
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Curr Mol Pharmacol, 2017,
10,
334-344.
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PubMed id
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Abstract
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The structural analysis of class B G protein-coupled receptors (GPCR), cell
surface proteins responding to peptide hormones, has until recently been
restricted to the extracellular domain (ECD). Corticotropin-releasing factor
receptor type 1 (CRF1R) is a class B receptor mediating stress response and also
considered a drug target for depression and anxiety. Here we report the crystal
structure of the transmembrane domain of human CRF1R in complex with the
small-molecule antagonist CP-376395 in a hexagonal setting with translational
non-crystallographic symmetry. Molecular dynamics and metadynamics simulations
on this novel structure and the existing TMD structure for CRF1R provides
insight as to how the small molecule ligand gains access to the induced-fit
allosteric binding site with implications for the observed selectivity against
CRF2R. Furthermore, molecular dynamics simulations performed using a full-length
receptor model point to key interactions between the ECD and extracellular loop
3 of the TMD providing insight into the full inactive state of multidomain class
B GPCRs.
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