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Photolabeling study of the ligand binding domain of natriuretic peptide receptor A: development of a model.

Abstract : Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are loop-shaped peptidic hormones that have multiple actions on body fluid homeostasis. Their physiological effects are mediated through the activation of their receptor, natriuretic peptide receptor A (NPRA). This receptor is a member of the membrane guanylyl cyclase family and catalyzes cyclic guanosine monophosphate (cGMP) production following its activation. To map the binding site of human NPRA, we applied the methionine proximity assay method to this receptor. We photolabeled NPRA mutants, presenting a single methionine in the binding domain of the receptor, and used benzoylphenylalanine- (Bpa-) substituted peptides at positions 0, 3, 18, 26, and 28 of the ligand. We identified that the N-terminus of the peptide is interacting with the region between Asp(177) and Val(183) of the receptor. Arg(3) is interacting in the vicinity of Phe(172). Leu(18) binds close to Val(116). Phe(26) binds in the vicinity of His(195), and the C-terminal Tyr(28) is located close to Met(173). We next proceeded with photolabeling of a dual Bpa-substituted peptide and showed that the N-terminus and Leu(18) interact with opposite receptor subunits. On the basis of our results, a molecular model of peptide-bound NPRA was developed by homology modeling with the C-type natriuretic peptide- (CNP-) bound natriuretic peptide receptor C (NPRC) crystal structure. The model has been validated by molecular dynamics simulations. Our work provides a rational basis for interpreting and predicting natriuretic peptide binding to the human NPRA.
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Contributor : Charles M. Dozois Connect in order to contact the contributor
Submitted on : Friday, May 3, 2013 - 1:02:14 AM
Last modification on : Monday, July 20, 2020 - 12:33:14 PM

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Christian Jossart, Martin Coupal, Normand Mcnicoll, Alain Fournier, Brian C Wilkes, et al.. Photolabeling study of the ligand binding domain of natriuretic peptide receptor A: development of a model.. Biochemistry, American Chemical Society, 2005, 44 (7), pp.2397-408. ⟨10.1021/bi048251y⟩. ⟨pasteur-00820032⟩



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