PDBsum entry 1jdp

Signaling protein

PDB id: 1jdp

Contents

Protein chains

396 a.a. *

18 a.a. *

Ligands

NAG-NAG

NAG ×3

Metals

_CL ×2

Waters ×470

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Allosteric activation of a spring-Loaded natriuretic peptide receptor dimer by hormone.

Authors

He xl, Chow dc, M.M.Martick, K.C.Garcia.

Ref.

Science, 2001, 293, 1657-1662. [DOI no: 10.1126/science.1062246]

PubMed id

11533490

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.

Figure 3.
Fig. 3. Conformational changes in the NPR-C complex and the molecular spring. (A) Backbone representations of bound (cyan) versus unliganded (purple) NPR-C (the peptide in the middle is shown in red). At the base of the structures, the width of the gap separating the COOH-terminal domains of the dimer in bound versus free form is indicated. The identical amino acid closest to the COOH-terminal at the base of the gap (Ala^208) was used in both structures as the point from which to measure the gap to the dimeric-related residue (Ala^208*). For the elbow angle of the structures, identical reference points (a vector defining an helix in the membrane-distal and -proximal domains) were chosen in bound versus free structures from which to measure an interdomain angle. (B) The spring tethering the membrane-distal and -proximal domains in each monomer is stretched and lengthened by 2.5 Å in the bound structure (40). A ribbon representation is shown of the linker peptide, along with the secondary structure elements leading up to and away from the peptide. The loose structure of the unbound peptide is obvious as compared with the straightened peptide in the complex. (C) The N-linked glycan at Asp248 forms extensive interactions with the linker peptide, which are broken upon hormone binding and conformational change (40). A stick representation of the peptide, the N-linked glycan, and the surrounding amino acids is shown. We have superimposed the Fo-Fc SIGMAA-weighted omit maps, at 2.9 Å (left) and 2.0 Å (right) of the NH[2]-linked glycan, to demonstrate the clarity of the carbohydrate conformational change.

Figure 4.
Fig. 4. Asymmetry of the hormone/receptor interfaces and the conformation of CNP. (A) Stick representation of the bound CNP peptide (orange) and the interacting amino acids from each NPR-C monomer (cyan and green) (40). The yellow spheres represent the bound chloride ions in each monomer. Ile^188, which has been shown to modulate the ligand pharmacology of NPR-C (37), is next to the CNP residue Phe^7, and is labeled in black. (B) This interface is then shown in an "open-book" view of the molecular surface of each receptor monomer. The CNP peptide is shown as a yellow backbone-and-stick model projected onto the respective buried surfaces (red patches) of each NPR-C monomer. The figures were drawn with BOBSCRIPT, RASTER3D, and VMD (41).

The above figures are reprinted by permission from the AAAs: Science (2001, 293, 1657-1662) copyright 2001.