Abstract
Natriuretic peptides (NPs) are vasoactive cyclic-peptide hormones important in blood pressure regulation through interaction with natriuretic cell-surface receptors. We report the hormone-binding thermodynamics and crystal structures at 2.9 and 2.0 angstroms, respectively, of the extracellular domain of the unliganded human NP receptor (NPR-C) and its complex with CNP, a 22-amino acid NP. A single CNP molecule is bound in the interface of an NPR-C dimer, resulting in asymmetric interactions between the hormone and the symmetrically related receptors. Hormone binding induces a 20 angstrom closure between the membrane-proximal domains of the dimer. In each monomer, the opening of an interdomain cleft, which is tethered together by a linker peptide acting as a molecular spring, is likely a conserved allosteric trigger for intracellular signaling by the natriuretic receptor family.
MeSH terms
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Allosteric Regulation
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Amino Acid Sequence
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Animals
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Atrial Natriuretic Factor / metabolism
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Binding Sites
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Calorimetry
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Cell Line
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Chlorides / metabolism
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Crystallization
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Crystallography, X-Ray
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Dimerization
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Drosophila
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Glycosylation
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Guanylate Cyclase / chemistry*
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Guanylate Cyclase / metabolism*
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Humans
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Hydrogen Bonding
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Natriuretic Peptide, Brain / metabolism
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Natriuretic Peptide, C-Type / chemistry
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Natriuretic Peptide, C-Type / metabolism*
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Protein Conformation
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Protein Folding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptors, Atrial Natriuretic Factor / chemistry*
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Receptors, Atrial Natriuretic Factor / metabolism*
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Thermodynamics
Substances
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Chlorides
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Ligands
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Natriuretic Peptide, Brain
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Natriuretic Peptide, C-Type
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Atrial Natriuretic Factor
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Guanylate Cyclase
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Receptors, Atrial Natriuretic Factor
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atrial natriuretic factor receptor C