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Science 293 (5535): 1657-1662

Copyright © 2001 by the American Association for the Advancement of Science

Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone

Xiao-lin He, Dar-chone Chow, Monika M. Martick, K. Christopher Garcia*

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.

Departments of Microbiology and Immunology and Structural Biology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 93405-5124, USA.
*   To whom correspondence should be addressed. E-mail: kcgarcia{at}stanford.edu


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