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Solution structure of human calcitonin in membrane‐mimetic environment: The role of the amphipathic helix
Author(s) -
Motta Andrea,
Andreotti Giuseppina,
Amodeo Pietro,
Strazzullo Giuseppe,
Morelli Maria A. Castiglione
Publication year - 1998
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19980815)32:3<314::aid-prot7>3.0.co;2-h
Subject(s) - chemistry , two dimensional nuclear magnetic resonance spectroscopy , amphiphile , nuclear overhauser effect , amide , nuclear magnetic resonance spectroscopy , helix (gastropod) , micelle , crystallography , molecule , spectroscopy , hydrogen bond , stereochemistry , organic chemistry , aqueous solution , copolymer , ecology , physics , quantum mechanics , snail , biology , polymer
The 32 amino acid hormone human calcitonin was studied at pH 3.7 and 7.4 by multidimensional NMR spectroscopy in sodium dodecyl sulfate micelles at 310K. The secondary structure was obtained from nuclear Overhauser enhancement spectroscopy (NOESY), 3 J HNα coupling constants, and slowly exchanging amide data. Three‐dimensional structures consistent with NMR data were generated by using distance geometry calculations. A set of 265 interproton distances derived from NOESY experiments, hydrogen‐bond constraints obtained from amide exchange, and coupling constants were used. From the initial random conformations, 30 distance geometry structures with minimal violations were selected for further refinement with restrained energy minimization. In micelles, at both pHs, the hormone assumes an amphipathic α‐helix from Leu9 to Phe16, followed by a type‐I β‐turn between residues Phe16 and Phe19. From His20 onward the molecule is extended and no interaction with the helix was observed. The relevance of the amphipathic helix for the structure–activity relationship, the possible mechanisms of interaction with the receptor, as well as the formation of fibrillar aggregates, is discussed. Proteins 32:314–323, 1998. © 1998 Wiley‐Liss, Inc.