Two Offprints on the Structure of Insulin; La Structure de l'Insuline [and] The Disulphide Bonds of Insulin

Sanger, Frederick

Publication Date: 1955

About this Item

Sanger received the Nobel Prize in Chemistry in 1958 for determining the complete amino acid sequence of insulin (the first protein ever to have its primary structure fully established) and a second in 1980 for developing methods for sequencing DNA, making him one of only four individuals ever to have received two Nobel Prizes. The two offprints offered here, both signed by Sanger, together constitute the complete published record of that first achievement: a synthetic lecture delivered in Marseille in December 1954 presenting the full sequential strategy by which insulin's structure was approached, and the definitive experimental paper establishing the positions of its three disulphide bridges-the final structural question the sequence work had left open. In demonstrating that a protein possesses a unique, fully definable covalent sequence, Sanger established the conceptual and methodological foundation upon which all subsequent structural biology rests. The principle that biological function is encoded in a specific primary sequence underlies every protein sequenced since, every therapeutic protein produced by recombinant technology, and every drug designed to interact with a defined molecular target; and the sequential degradation strategy Sanger developed for insulin was the direct intellectual precursor of the DNA sequencing methodology for which he received his second Nobel Prize; and which in turn made the Human Genome Project possible. (1) La Structure de l'Insuline; from Bulletin de la Société de Chimie biologique, Tome XXXVII, no. 1, pp.23-35. Paris: Masson et Cie, 1955. Offprint, 8vo (242 x 159mm), pp. 13, [3]. Original blue printed wrappers, staple-bound, some toning and rubbing, else near fine. Signed by Sanger on the front wrapper. A lecture delivered on 13 December 1954 in Marseille, in which Sanger presents a synthetic account of the decade-long experimental program at the Department of Biochemistry, University of Cambridge, that resulted in the complete elucidation of the amino acid sequence of insulin; the first protein ever to have its primary structure fully determined. Setting aside earlier disputed molecular weight values in favor of a minimum covalent unit of 6,000 (later calculated at 5,734), Sanger describes the sequential strategy by which the complete structure was approached: first, the identification of two N-terminal residues (DNP-glycine and DNP-phenylalanine, one equivalent of each) using the fluorodinitrobenzene reagent he had himself introduced in 1945, establishing that insulin comprises two distinct polypeptide chains; then the separation of those chains by performic acid oxidation, which cleaved the cystine disulfide bridges and resolved the molecule into a glycyl chain A of approximately 20 residues and a phenylalanyl chain B of approximately 30; then the stepwise determination of the N-terminal sequences of both chains by partial hydrolysis and partition chromatography, establishing that chain B begins Phe.Val.Asp.Glu and chain A begins Gly.Ileu.Val.Glu.Glu; and finally the mapping of the disulfide bridge positions, including an intrachain ring at positions A6 and A11 whose dimensions Sanger notes are shared by oxytocin and vasopressin, and the two interchain bridges connecting A and B, determined through systematic chymotryptic and peptic hydrolysis under conditions preventing disulfide exchange. The significance of the work extends far beyond insulin: in demonstrating that a protein possesses a unique, fully definable covalent sequence, Sanger established the conceptual and methodological foundation upon which all subsequent structural biology rests, and the principle that biological function is encoded in a specific primary sequence underlies every protein sequenced since, every therapeutic protein produced by recombinant technology, and every drug designed to interact with a defined molecular target. Sanger received the Nobel Prize in Chemistry in 1958 for this work, and a second in 1.

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Bibliographic Details

• Title: Two Offprints on the Structure of Insulin; La Structure de l'Insuline [and] The Disulphide Bonds of Insulin
• Publication Date: 1955
• Edition: First Edition.
• Signed: Signed
• Seller catalogs:
  • Medicine