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Summary Article: Perutz, Max Ferdinand
from Encyclopedia of Life Sciences

1914-2002 Austrian-born British biochemist who determined the structure of the oxygen-binding protein haemoglobin by X-ray diffraction analysis.



X-ray diffraction




sickle cell anaemia

Perutz was born in Vienna, Austria on 19 May 1914. Educated at the University of Vienna, he became interested in biochemistry and wanted to enter Gowland Hopkins's laboratory at Cambridge. Herman Mark, Professor of Physical Chemistry in Vienna, was impressed by J. D. Bernal's X-ray diffraction work and persuaded Perutz to join Bernal's laboratory at Cambridge instead. In September 1936 he began his graduate studies on the structure of minerals, but during the summer vacation in 1937 Perutz met the Austrian biochemist Felix Haurowitz, who suggested that he should investigate the structure of haemoglobin. This was valuable advice as Cambridge has a long tradition of haemoglobin research from Joseph Barcroft's work on its oxygen equilibrium curve in 1907 to David Keilin's work on cell respiration, haem proteins and the cytochromes. G. S. Adair, the Cambridge physiologist, gave Perutz a sample of horse methaemoglobin, the oxidized form of haemoglobin, and with this Perutz began his X-ray diffraction studies. See also X-ray Diffraction: Principles, Barcroft, Joseph, and Keilin, David

Haemoglobin crystals produce good X-ray patterns and by determining the dimensions of the unit cell, Perutz concluded that the molecule was a dimer with two identical halves.

Bernal moved to Birkbeck College, London in 1938 and Lawrence Bragg became the new Cavendish Professor of Physics. Bragg was excited by the prospect of applying X-ray techniques to large protein molecules and secured a grant from the Rockefeller Foundation to allow Perutz to continue his work; he received his doctorate in 1940. His career was then interrupted due to the war. He had to obtain a residence permit for his parents who had fled from Nazi persecution and was himself interned as an enemy alien for six months. In 1943 he was required to help in an absurd project to build a gigantic aircraft carrier made of ice.

After the war Perutz directed a Medical Research Council Unit in Cambridge supported by his only student, J. C. Kendrew. The interpretation of his X-ray photographs posed problems because they contained the intensities but not the phases of the diffracted rays without which it was impossible to determine the structure. Perutz solved this problem in 1954, using a method of isomorphous replacement with heavy atoms first applied to the alums in Bragg's laboratory at Manchester. By attaching mercury and gold or silver atoms to the haemoglobin molecule and comparing the X-ray diffraction patterns with those of the pure protein, the phases could be determined. During the next five years Perutz obtained X-ray data for six isomorphous derivatives with heavy metal atoms at different positions and by 1959 he was able to construct a three-dimensional map of the haemoglobin molecule. He showed that it was composed of four separate polypeptide chains forming a tetrahedral structure, with four haem groups enclosed in pockets of the globin near the molecule's surface. The fold of the chains in haemoglobin resembled that of Kendrew's structure for myoglobin from sperm whale muscle, determined two years earlier. Perutz's method opened up protein crystallography and has been extended to several hundred other proteins, enzymes, antibodies and viruses. See also Kendrew, John Cowdery, and Macromolecular Structure Determination by X-ray Crystallography

In 1962 Perutz shared the Nobel Prize for Chemistry with J. C. Kendrew. Having determined the structure of haemoglobin, he continued to study its properties. The sigmoidal shape of its oxygen equilibrium curve had been attributed to interaction between the haem groups, but their wide separation made it difficult to imagine easy interaction between them. Perutz therefore turned to Haurowitz's 1938 observation that crystals of oxy- and deoxyhaemoglobin have different symmetries, suggesting a change in structure during the take-up and release of oxygen. At the Pasteur Institute in Paris in the early 1960s, Jacques Monod, François Jacob and Jean-Pierre Changeux suggested that the sigmoid curve arose from allosteric behaviour in which the binding of the first molecule of oxygen makes the take-up of subsequent molecules easier. Monod suggested that complex proteins, made up of several subunits, can exist in two or more reversible arrangements, a relaxed structure (R) in which the subunits are unconstrained and a tense structure (T) in which they are linked by additional bonds. See also Protein Quaternary Structure: Symmetry Patterns

In 1962 Perutz and Hilary Muirhead found that the change in crystal form was due to a rearrangement of α and β subunits during the binding and release of oxygen. The mechanism was unknown until 1970 when the constraints in the T structure predicted by Monod were found to be salt bridges between the subunits broken on transition to the R structure triggered by movement of the iron atoms relative to the porphyrin, the conjugated protein group. In deoxyhaemoglobin the iron is displaced from the plane of the porphyrin group and the molecule becomes dome-shaped; in oxyhaemoglobin the iron lies in a plane with the porphyrin. An electronic transition and change of coordination of the iron is also involved. In deoxyhaemoglobin the iron is five-coordinated and in high spin, whereas in oxyhaemoglobin the iron is six-coordinated and in low spin. Perutz predicted that there should be a reciprocal relationship between the spin-state of the iron and the two structures of haemoglobin and this was later confirmed. The transfer of oxygen to the tissues and return transport of carbon dioxide back to the lungs depends on the take-up of protons to convert carbon dioxide to soluble bicarbonate, a process reversed in the lungs. With J. V. Kilmartin, Perutz showed that the uptake and release of protons is linked to the formation of salt bridges in the T structure of haemoglobin and their rupture in the R structure.

Perutz also studied mutant forms of haemoglobin characteristic of certain diseases such as sickle cell anaemia. In 1956, Vernon Ingram, a protein chemist working with Perutz and Kendrew, found that sickle cell haemoglobin differs from the normal form by the replacement of one pair of valine residues by glutamine acid. Perutz was later asked to develop anti-sickling agents using X-ray analysis to determine their binding sites. This work led him to formulate general rules governing the interaction of drugs with proteins. See also Sickle Cell Anaemia, and Receptor Binding in Drug Discovery

Perutz also investigated the formation of glacial ice and the speed of flow of glaciers. He found that the surface of a glacier moves faster than its base. He later became interested in the effects of science on society, expressing his views in several books and articles.

Further Reading
  • Perutz, MF (1963) X-ray analysis of haemoglobin (Nobel Address). Science 140: 863-869.
  • Perutz, MF (1978) Haemoglobin structure and respiratory transport. Scientific American 239: 92-125.
  • Perutz, MF (1980) Origins of molecular biology. New Scientist 85: 326-329.
  • Perutz, MF (1981) A sagacious scientist. New Scientist 90: 39.
  • Perutz, MF (1989) Is Science Necessary? Essays on Science and Scientists. New York: Dutton.
  • Perutz, MF (1998) I Wish I'd Made You Angry Earlier: Essays on Science, Scientists and Humanity. Plainview, NY: Cold Spring Harbor Laboratory Press.
  • Hagan, WJ (1993) In: James, LK (ed.) Nobel Laureates in Chemistry 1901-1992, (History of Modern Chemistry Series), pp 425-441. Washington DC: American Chemical Society and the Chemical Heritage Foundation.
  • Noel G Coley
    The Open University Milton Keynes, UK
    Wiley ©2007

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