Structural Determinants of Natriuretic Peptide Receptor Specificity and Degeneracy

Xiao, He; Dukkipati, Abhiram; García, K. Christopher

doi:10.1016/j.jmb.2006.06.060

Cited by 66 publications

(73 citation statements)

References 38 publications

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“…ANP binds GC-A at a stoichiometry of 1:2 and induces a rotation of the juxtamembrane region (3,4). Structural modeling studies suggest that CNP binds GC-B similarly (5,6). Natriuretic peptide binding is hypothesized to activate the receptors by relieving basal repression exerted by the kinase homology domains on the guanylyl cyclase domains (7,8).…”

Section: Natriuretic Peptides and Atp Activate And Gö6976 Inhibits Gumentioning

confidence: 99%

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

Robinson

Potter

2011

Journal of Biological Chemistry

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Natriuretic peptides and ATP activate and Gö6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Gö6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 M for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 M Gö6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550 -2553), neither staurosporine nor Gö6976 activated GC-A or GC-B. This is the first study to show that Gö6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Gö6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.

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Section: Natriuretic Peptides and Atp Activate And Gö6976 Inhibits Gumentioning

confidence: 99%

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

Robinson

Potter

2011

Journal of Biological Chemistry

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“…6, B and C; Table 3). Two outstanding regions of the ligand binding interface of natriuretic peptide receptors involve hydrophobic regions (He et al, 2006 (Fig. 6B).…”

Section: Dimerization Of Npra Extracellular Domain 435mentioning

confidence: 99%

Role of Extracellular Domain Dimerization in Agonist-Induced Activation of Natriuretic Peptide Receptor A

Parat¹,

McNicoll²,

Wilkes³

et al. 2007

Mol Pharmacol

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Natriuretic peptide receptor (NPR)A is composed of an extracellular domain (ECD) with a ligand binding site, a single transmembrane region, a kinase homology domain, and a guanylyl cyclase domain. The natural agonists atrial and brain natriuretic peptides (ANP, BNP) bind and activate NPRA, leading to cyclic GMP production, which is responsible for their role in cardiovascular homeostasis. Previous studies suggested that stabilization of a dimeric form of NPRA by agonist is essential for receptor activation. However, ligand specificity and sequential steps of this dimerization process have not been investigated. We used radioligand binding, fluorescence resonance energy transfer homoquenching, and molecular modeling to characterize the interaction of human NPRA-ECD with ANP, BNP, the superagonist (Arg 10 ,Leu 12 ,Ser 17 ,Leu 18 )-rANP-(1-28), the minimized analog mini-ANP and the antagonist (Arg 6 ,␤-cyclohexylAla 8 ,D-Tic 16 ,Arg 17 ,Cys 18 )-rANP-(6 -18)-amide (A71915). ANP binds to preformed ECD dimers and spontaneous dimerization is the rate-limiting step of the ligand binding process. All the studied peptides, including A71915 antagonist, induce a dosedependent fluorescence homoquenching, specific to dimerization, with potencies highly correlated with their binding affinities. A71915 induced more quenching than other peptides, suggesting stabilization by the antagonist of ECD dimer in a distinct inactive conformation. In summary, these results indicate that the ligand-induced dimerization process of NPRA is different from that for cytokine receptor model. Agonists or antagonists bind to preformed dimeric ECD, leading to dimer stabilization in an active or inactive conformation, respectively. Furthermore, the highly sensitive fluorescence assay designed to assess dimerization could serve as a powerful tool for further detailing the kinetic steps involved in natriuretic peptide receptor binding and activation.

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“…A previous molecular model of human NPR-B complexed to CNP was created by He and colleagues [14], which focused on interactions that provided ligand specificity. The mutation in CNP lbab occurs in a highly conserved region, which was not discussed in the previous model.…”

Section: Discussionmentioning

confidence: 99%

Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab−/− mice

et al. 2008

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C-type natriuretic peptide (CNP) stimulates endochondrial ossification by activating the transmembrane guanylyl cyclase, natriuretic peptide receptor-B (NPR-B). Recently, a spontaneous autosomal recessive mutation that causes severe dwarfism in mice was identified. The mutant, called long bone abnormality (lbab), contains a single point mutation that converts an arginine to a glycine in a conserved coding region of the CNP gene, but how this mutation affects CNP activity has not been reported. Here, we determined that thirty to greater than one hundred-fold more CNP lbab was required to activate NPR-B as compared to wild-type CNP in whole cell cGMP elevation and membrane guanylyl cyclase assays. The reduced ability of CNP lbab to activate NPR-B was explained, at least in part, by decreased binding since ten-fold more CNP lbab than wild-type CNP was required to compete with [ 125 I][Tyr 0 ]CNP for receptor binding. Molecular modeling suggested that the conserved arginine is critical for binding to an equally conserved acidic pocket in NPR-B. These results indicate that reduced binding to and activation of NPR-B causes dwarfism in lbab −/− mice.

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Structural Determinants of Natriuretic Peptide Receptor Specificity and Degeneracy

Cited by 66 publications

References 38 publications

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

ATP Potentiates Competitive Inhibition of Guanylyl Cyclase A and B by the Staurosporine Analog, Gö6976

Role of Extracellular Domain Dimerization in Agonist-Induced Activation of Natriuretic Peptide Receptor A

Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab−/− mice

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