Crystals and X-rays: biological macromolecules

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PANEL_08.inddThe capacity of crystallography to reveal ever larger and more complex molecular structures is unstoppable. In half a century we have gone from the discovery of the structure of nucleic acids and the mechanism of genetic transfer, to solving the atomic structures of the active centres of large proteins and macromolecular complexes, something which is at the basis of the latest medical and pharmacological advances. Out of this knowledge a new science was born: Structural Biology. The vault particle of the cellular nucleus membrane that the figure illustrates is larger than the ribosome, and could be involved in the transport of nucleic acids, protein synthesis and, possibly, resistance to chemotherapy treatments.



In 1953 one of the discoveries that marked science in the second half of the twentieth century and the future of biology and medicine was made. James Watson and Francis Crick at Cambridge University and Rosalind Franklin and Maurice Wilkins at King’s College, London, were working on solving the structure of deoxyribonucleic acid (DNA). Both had purified and crystallized DNA but Rosalind Franklin had obtained the best X-ray diffraction images, among them her photo 51, which showed that the structure must be a double helix. This photo 51 served as inspiration for Watson and Crick to interpret precisely and correctly how the sugars, the bases and the phosphates are assembled in that double helix.


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Diffraction pattern of the form B of DNA taken by Rosalind Franklin Francis Crick and James Watson with their proposal of DNA structure. Structure of the double helix of DNA.

It was a brilliant job that amazed the scientific world. Moreover, in this case the importance of crystallography was made evident, given that there was no better molecule than DNA to explain the relation between structure and function. The whole world understood what the authors of the work themselves concluded, that “the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” There was a clear relation between the structures of the biological macromolecules and the function they performed in the organism. A new science had been born: structural biology.

Watson, Crick and Wilkins received the Nobel Prize for Chemistry in 1962. Rosalind Franklin had died four years previously.

The problem of crystallization

In order to solve any macromolecular structure, first it is necessary to obtain its crystals. It must be crystalized. This is done using solutions of these substances, whether they are proteins, nucleic acids or large macromolecular complexes. Unfortunately, crystallization is so complicated that at times it proves to be the bottleneck of large Structural Biology and Biomedicine projects. In 1946 James Batcheller Sumner received the Nobel Prize for Chemistry for the discovery of the crystallization of proteins and in 1988 Hartmut Michel shared the Nobel Prize for Chemistry for his contribution to the crystallization of membrane proteins and, specifically, the photosynthetic reaction centre.


Thaumatin crystals in a counterdiffusion capillary. Apoferritin crystal obtained in agarose gels.

The width of these crystals is 800 microns. Nowadays crystals just a few microns wide are used to obtain X-ray diffraction images.

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Structure of the human antibody IgG1 b12 that recognises specific sites of the immunodeficiency virus HIV-1 and is capable of neutralizing it. This antibody has been studied for the development of vaccines against AIDS. C05 is an antibody that attaches to a protein on the coat of the flu virus (represented in red in the figure) and which is highly efficient and selective, for which reason it is the subject of research to find better vaccines against the most dangerous types of flu.


Ribosomes are large macromolecular complexes composed of ribonucleic acid and proteins responsible for the production of proteins in all living cells. Their size is enormous. To get an idea of their size and complexity, take the mass of a molecule of sodium chloride, which is 60 Dalton (Da), or penicillin at 350 Da, even human insulin, which is some 5,800 Da, and compare them with the molecular weight of ribosome, which is 2,500,000 Da. Understanding the protein synthesis processes in the ribosome, its later folding and its degradation in the proteasome, is making it possible to advance the understanding of neurodegenerative diseases such as Alzheimer’s. Resolving the structure of this immense molecular machine has been one of the latest achievements of crystallography. The 2009 Nobel Prize for Chemistry was awarded to Venkatraman Ramakrishnan, Thomas A. Steitz and Ada E. Yonath for their work on the structure and function of ribosome.

Mini-documentary on the life and work of Ada E. Yonath.










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