Solving the Structure of Insulin
| Category | Research |
|---|---|
| Also known as | Sanger insulin, Hodgkin insulin crystal structure, first protein sequence |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | historyinsulinSangerHodgkincrystallography |
Overview
Insulin holds a special place in the history of structural biology. In 1955, Frederick Sanger at the University of Cambridge published the complete amino acid sequence of bovine insulin, establishing for the first time that proteins have defined, repeatable primary structures and setting the template for all later protein sequencing. In 1969, Dorothy Crowfoot Hodgkin and her collaborators at the University of Oxford published the three-dimensional crystal structure of insulin, a project that had occupied Hodgkin for more than three decades.
Together, these achievements transformed insulin from a clinical substance of known potency but uncertain identity into a fully characterized molecule. They also earned their principal investigators Nobel Prizes — Sanger in 1958 for chemistry (his first of two) and Hodgkin in 1964 for chemistry (for her broader crystallographic work, including penicillin and vitamin B12).
The structural work mattered for two reasons. First, it answered the fundamental scientific question of whether a protein has a single, reproducible sequence. Second, it laid the groundwork for the rational design of insulin analogs — synthetic variants with altered pharmacokinetics — that now dominate diabetes therapy.
Key People
- Frederick Sanger (1918–2013): British biochemist who sequenced insulin, earning his first Nobel Prize in 1958.
- Dorothy Crowfoot Hodgkin (1910–1994): British chemist who solved the crystal structure of insulin.
- Ted Ryle, Hans Tuppy, Leslie Smith: Sanger's collaborators on the chemical sequencing work.
- Guy Dodson, Eleanor Dodson, Tom Blundell: Crystallographers who worked with Hodgkin on insulin.
Timeline
- 1934: Hodgkin obtains the first crystals of insulin.
- 1943–1955: Sanger develops dinitrofluorobenzene and partial acid hydrolysis methods to sequence insulin.
- 1951–1952: Sanger reports the sequence of insulin's two chains.
- 1955: Complete sequence of insulin, including disulfide bridges, is published.
- 1958: Sanger receives the Nobel Prize in Chemistry.
- 1964: Hodgkin receives the Nobel Prize in Chemistry.
- 1969: Three-dimensional structure of insulin is published.
Background
Sanger chose insulin for sequencing work because it was relatively small (51 amino acids in two chains), available in pure form (thanks to the commercial production initiated after the Banting-Best discovery), and of obvious biomedical importance. His key technical innovation was a reagent — 2,4-dinitrofluorobenzene, later known as "Sanger's reagent" — that labeled the free amino-terminal residue of a peptide. By combining labeling, partial hydrolysis, and careful chromatographic separation, he reconstructed the entire sequence.
Hodgkin's structural work relied on a different toolkit: X-ray crystallography, a field she had helped build through earlier solutions of penicillin and vitamin B12 structures. Insulin proved a formidable target because of its size, complex crystal packing, and tendency to form hexameric assemblies around zinc ions. Her perseverance, together with computational advances in the 1960s, finally produced the iconic three-dimensional model.
Modern Relevance
The combined sequence and structure of insulin made it possible to engineer insulin analogs with tailored properties. Rapid-acting analogs such as insulin lispro, aspart, and glulisine modify amino acids at the monomer-monomer interface to discourage hexamer formation, speeding absorption. Long-acting analogs such as insulin glargine and detemir use different strategies — shifted isoelectric points or fatty-acid conjugation — to prolong the duration of action. All these designs are direct descendants of the Sanger–Hodgkin structural framework.
Insulin remains a model system for peptide chemistry, protein folding, and structural biology. Modern research on proinsulin, amylin, and emerging "smart insulin" concepts continues to rely on the architectural blueprint laid down in 1955 and 1969. For broader historical context, see first-recombinant-insulin.
Related Compounds
Related entries
- Banting and Best: The Discovery of Insulin— How Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip isolated insulin in 1921 at the University of Toronto.
- The First Recombinant Insulin— Humulin, the first recombinant human insulin, was approved in 1982 after being expressed in E. coli by Genentech and developed with Eli Lilly.
- Frederick Sanger— Frederick Sanger was the British biochemist who sequenced insulin in 1955 and later developed DNA sequencing, earning two Nobel Prizes in Chemistry.