Highest impact structures

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Two Types of "Impact"

Macromolecular 3D structures can impact scientific understanding and/or save lives by contributing to Structure-based drug design. The first list below, Highest Impact Macromolecular Structures of All Time, concerns impact on scientific understanding. A separate list below concerns Structures Saving The Most Lives.

Highest Impact Macromolecular Structures of All Time

Below you are invited to list pages about structures that you believe to be among the highest impact since the first empirical macromolecular structures were determined. Please do not list a structure unless you provide a justification in the form of a brief description of its impact.

More about some of the earliest structures and their PDB files is here.

This list is in chronological order.

20th Century

  • 1953 - DNA double helix (B form): Although Watson and Crick's model was theoretical, it was essentially correct, and for the first time explained the ability of genes to be faithfully copied during cell division. It was not confirmed by atomic resolution X-ray crystallography until 1973, using RNA dinucleotide crystals. A full turn of B form DNA was not solved until 1980 (cf. 1bna), 27 years after Watson and Crick's model. More: click on DNA at the Atlas of Macromolecules
  • 1958 - Myoglobin: As the first protein structure that was determined, it is hard to exaggerate its impact. Before this structure, proteins were widely believed to be colloidal, and protein crystals were expected to contain highly symmetrical structures. The irregular fold of myoglobin (see photo of an early low-resolution model at Nobel Prizes for 3D Molecular Structure) was a huge surprise.
  • 1965 - Lysozyme: The first enzyme crystal structure determination and the third protein structure overall. The structure provided the first view of a beta-sheet, and the first view of the three-dimensional arrangement of catalytic amino acid residues in an active site.[1] An inhibitor-bound structure determined in the same year showed the non-covalent interactions between binding cleft and the ligand. Lysozyme is a model enzyme for studying crystallization, the impact of crystal packing on structure, catalytic activity in the crystalline state, and the consequences of mutations on structure and activity. (See lysozyme.)
  • 1969 - Insulin: The insulin structure was solved in 1969 by Dorothy Hodgkin, a pioneering X-ray crystallographer who had previously won the Nobel prize for her work on vitamin B12[2]. Insulin itself is used as a live-saving drug to treat type 1 diabetes. Using the structure of hexameric insulin (the storage form) as guidance, variations of insulin were developed that are fast-acting or slow-acting.
  • 1970 - Deoxy-hemoglobin: M. Perutz' second hemoglobin structure proved to be at least as important as the first, published two years earlier, as it demonstrated that a protein can have several conformations, and that its physiological role depends on how it changes from one to the other. (See Hemoglobin.)
  • 1974 - Transfer RNA: The first 3D RNA structure solved; tRNA remained the only biological RNA solved crystallographically for around two decades. This landmark structure served as a foundation for our understanding of RNA structure and translation in general[3].
  • 1978 - Tobacco bushy stunt virus: S. Harrison offered the first atomic scale image of a complete biological object, a plant virus. It was a technical feat, and revealed rules of architecture that, a few years later (1985), were shown to apply to human pathogens such as the common cold and the poliomyelitis viruses.
  • 1983 - Keratin: Israel Hanukoglu determined the primary structures and predicted secondary structures of type and type II keratins as a postdoc in the lab of Elaine Fuchs at the University of Chicago.[4] His analyses served as models for all intermediate family proteins, and were confirmed by crystallography of soluble keratin fragments nearly 30 years later.[5]
  • 1987 - Major histocompatibility complex class I: Created a paradigm shift in cellular immunology by explaining how MHC is involved in presenting hidden intracellular proteins to T lymphocytes. During the decade prior to this structure, this was a constantly debated but very murky mystery.

21st Century

  • 2007 and 2011 - G protein-coupled receptor: In 2007 the structure of the first ligand-activated G protein-coupled receptor and in 2011 the first activated G protein-coupled receptor bound to its G protein. This is a large class of proteins that have great importance as targets for drug development; it is estimated that 4% of the human genome devoted to protein coding encodes this class of proteins. The determination of the structures lead to Brian Kobilika sharing the 2012 Nobel Prize in Chemistry
  • 2019 - Cytochrome nanowires: 6ef8 was the first structure of an electrically-conductive bacterial protein nanowire, confirmed by 6nef. Such nanowires appear to be important in global carbon and metal redox phenomena in anoxic soils and sediments, and have many possible applications[6][7][8]. Prior to these cryo-EM structures, it had been believed for over a decade that nanowires were type IV pili assembled from pilA[9]. These structures surprisingly revealed nanowires as polymers of 6-heme C-type cytochromes, which called this belief into question. The unexpected protein making up these nanowires was determined from the cryo-EM density map. This is an unusual case in which the protein making up an extensively-studied structure was not known prior to solving the structure.

Structures Saving The Most Lives

Structures of the following molecules were used in Structure-based drug design, and the resulting drugs have saved large numbers of lives.

  • The insulin structure was solved in 1969 by Dorothy Hodgkin, a pioneering X-ray crystallographer who had previously won the Nobel prize for her work on vitamin B12[2]. Insulin itself is used as a live-saving drug to treat type 1 diabetes. Using the structure of hexameric insulin (the storage form) as guidance, variations of insulin were developed that are fast-acting or slow-acting.


  • Influenza virus neuraminidase structure was used in designing the neuraminidase inhibitors oseltamivir (Tamiflu®) and zanamivir (Relenza®). Roche, the manufacturer of Tamiflu, estimates that 50 million people have been treated with this drug[10]. The Cochrane Collaboration concluded that neuriminidase inhibitors "are effective in preventing and treating the symptoms and complications of influenza"[11]. Influenza kills hundreds of thousands of people annually[12], including 40,000 in the United States[13]. While it is difficult to estimate accurately the number of lives saved by these drugs, the number seems likely to be very large.


See Also

References

  1. Lysozyme: A model enzyme in protein crystallography. NCJ Strynadka and MNG James in Lysozymes: Model Enzymes in Biochemistry and Biology By Pierre Jollès, Birkhäuser, 1996 ISBN 3764351217
  2. 2.0 2.1 https://www.nobelprize.org/prizes/chemistry/1964/hodgkin/biographical/
  3. Clark BF. The crystallization and structural determination of tRNA. Trends Biochem Sci. 2001 Aug;26(8):511-4. PMID:11504628
  4. Hanukoglu I, Fuchs E. The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins. Cell. 1983 Jul;33(3):915-24. PMID:6191871
  5. Lee CH, Kim MS, Chung BM, Leahy DJ, Coulombe PA. Structural basis for heteromeric assembly and perinuclear organization of keratin filaments. Nat Struct Mol Biol. 2012 Jun 17;19(7):707-15. doi: 10.1038/nsmb.2330. PMID:22705788 doi:10.1038/nsmb.2330
  6. Malvankar NS, Lovley DR. Microbial nanowires for bioenergy applications. Curr Opin Biotechnol. 2014 Jun;27:88-95. doi: 10.1016/j.copbio.2013.12.003. Epub , 2013 Dec 31. PMID:24863901 doi:http://dx.doi.org/10.1016/j.copbio.2013.12.003
  7. Lovley DR. Happy together: microbial communities that hook up to swap electrons. ISME J. 2017 Feb;11(2):327-336. doi: 10.1038/ismej.2016.136. Epub 2016 Nov 1. PMID:27801905 doi:http://dx.doi.org/10.1038/ismej.2016.136
  8. Filman DJ, Marino SF, Ward JE, Yang L, Mester Z, Bullitt E, Lovley DR, Strauss M. Cryo-EM reveals the structural basis of long-range electron transport in a cytochrome-based bacterial nanowire. Commun Biol. 2019 Jun 19;2:219. doi: 10.1038/s42003-019-0448-9. eCollection 2019. PMID:31240257 doi:http://dx.doi.org/10.1038/s42003-019-0448-9
  9. Wang F, Gu Y, O'Brien JP, Yi SM, Yalcin SE, Srikanth V, Shen C, Vu D, Ing NL, Hochbaum AI, Egelman EH, Malvankar NS. Structure of Microbial Nanowires Reveals Stacked Hemes that Transport Electrons over Micrometers. Cell. 2019 Apr 4;177(2):361-369.e10. doi: 10.1016/j.cell.2019.03.029. PMID:30951668 doi:http://dx.doi.org/10.1016/j.cell.2019.03.029
  10. Roche update on Tamiflu for pandemic influenza preparedness, Media Release, April 26, 2007.
  11. Neuraminidase inhibitors for preventing and treating influenza in healthy adults, T. Jefferson et al., Cochrane Database of Systematic Reviews, Issue 4, 2008. DOI 10.1002/14651858.CD001265.pub2
  12. Influenza in Wikipedia.
  13. Mortality due to Influenza in the United States—An Annualized Regression Approach Using Multiple-Cause Mortality Data, J. Dushoff et al., Am. J. Epidemiol. 163:181-7, 2006.

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