Science

Human CRFR2 alpha extracellular domain in complex with Urocortin 3 (PDB ID 3N93)

CRF plays a central role in coordinating endocrine, autonomic, and behavioral responses to stress via activation of CRFR1 in the brain. The CRF/Ucn families of peptides are 38–41 amino acids in length and have a C-terminal amide group that is strictly required for bioactivity. They include four structurally similar peptides, CRF, Ucn1, Ucn2, and Ucn3 and their two related class B G protein-coupled receptors, CRFR1 and CRFR2 which constitute an important biological system that controls central stress/anxiety responses, links stress and metabolic energy homeostasis, and regulates cardiovascular, immune, gastrointestinal, and reproductive functions.

The purified N-terminal extracellular domains (ECDs) of human CRFR1 and the CRFR2_ isoform are sufficient to discriminate the peptides. Ucn2 and Ucn3 are CRFR2-selective. They have recently emerged as important metabolic regulators that link stress and energy homeostasis. 3 crystal structures of the CRFR2_ ECD that bound to each of the Ucn peptides are studied. They show how the Ucn peptides are recognized by the CRFR2 receptor and reveal the structural basis for ligand discrimination by the CRFR1 and CRFR2 ECDs. Comparing the electrostatic surface potentials of the ECDs suggests a charge compatibility mechanism for ligand discrimination involving a single amino acid difference in the receptors. The structures explain the mechanisms of ligand recognition and discrimination and provide a molecular template for the rational design of therapeutic agents selectively targeting these receptors. lkh9023855

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