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Determination of the three-dimensional structure of adrenomedullin, a first step towards the analysis of its interactions with receptors and small molecules
Structural highlights
FunctionADML_HUMAN AM and PAMP are potent hypotensive and vasodilatator agents. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, am is diuretic and natriuretic, and both am and pamp inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion. Both peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in blood vessels. Publication Abstract from PubMedAdrenomedullin (AM) is a regulatory peptide which plays many physiological roles including vasodilatation, bronchodilatation, hormone secretion regulation, growth, apoptosis, angiogenesis, and antimicrobial activities, among others. These regulatory activities make AM a relevant player in the pathophysiology of important diseases such as cardiovascular and renal conditions, cancer, and diabetes. Therefore, molecules that target the AM system have been proposed as having therapeutic potential. To guide the design and characterization of such molecules we elucidated the three-dimensional structure of AM in a membrane mimicking medium using NMR spectroscopy methods. Under the employed experimental conditions, the structure can be described as composed by a central alpha-helical region, spanning about one third of its total length, flanked by two disordered segments at both N- and C-termini. The structure of AM in water is completely disordered. The 22-34 region of AM has a general tendency to adopt a helical structure under the employed experimental conditions. Furthermore, the study of the interaction of AM with two of its modulators has also been performed by using chemical shift perturbation analysis NMR methods with 2D-TOCSY experiments, assisted with molecular modelling protocols. We expect these results will help in better understanding the interactions of AM with its receptor and binding proteins/molecules and in the development of novel modulators of AM activities. (c) 2011 Wiley Periodicals, Inc. Biopolymers, 2011. Structure of micelle-bound adrenomedullin, a first step towards the analysis of its interactions with receptors and small molecules.,Perez-Castells J, Martin-Santamaria S, Nieto L, Ramos A, Martinez A, de Pascual-Teresa B, Jimenez-Barbero J Biopolymers. 2011 Aug 9. doi: 10.1002/bip.21700. PMID:21830197[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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