1gnb

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Revision as of 15:00, 12 November 2007

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DETERMINATION OF THE SOLUTION STRUCTURE OF THE PEPTIDE HORMONE GUANYLIN: OBSERVATION OF A NOVEL FORM OF TOPOLOGICAL STEREOISOMERISM

Overview

Guanylin is a 15 amino acid mammalian hormone containing two disulfide, bonds. Guanylin shares sequence similarity with the bacterial heat-stable, enterotoxin (STa) and is capable of binding to and stimulating the STa, guanylyl cyclase receptor. Biologically active peptides have been prepared, by two methods: (1) enzymatic treatment of a 99 residue proprotein, (denoted proguanylin) expressed in Escherichia coli and (2) solid-phase, chemical synthesis. Although both sources yield material that is pure by, high-performance liquid chromatography and mass spectrometry, analysis by, nuclear magnetic resonance (NMR) indicates that peptides from both sources, contain two conformationally distinct species present in a 1:1 ratio. The, chemical shift differences between the two species are large, allowing, unambiguous sequential NMR assignments to be made for both sets of, resonances. Exchange between the two forms was not observed even at 70, degrees C. Structural restraints have been generated from nuclear, Overhauser effects and scalar coupling constants and used to calculate, structures for both forms using distance geometry and restrained energy, minimization. The resulting structures for the first isoform are well, defined (root-mean-square deviation from the average structure for, backbone atoms of 0.47 A) and adopt a right-handed spiral conformation, similar to that observed for heat stable enterotoxin. The second isoform, is less well defined (root-mean-square deviation from the average, structure for backbone atoms of 1.07 A) but clearly adopts a very, different fold consisting of a left-hand spiral. The differences in, structure suggest that the two forms may have very different affinities, toward the STa receptor. The observation of such isomerism has important, implications for the common practice of introducing multiple disulfide, bonds into small peptides to limit conformational flexibility and enhance, bioactivity.

About this Structure

1GNB is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Determination of the solution structure of the peptide hormone guanylin: observation of a novel form of topological stereoisomerism., Skelton NJ, Garcia KC, Goeddel DV, Quan C, Burnier JP, Biochemistry. 1994 Nov 22;33(46):13581-92. PMID:7947768

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