Structural biology

Structural biology deals with structural analysis of living material (formed, composed of, and/or maintained and refined by living cells) at every level of organization.{{cite book |last1=Liljas |first1=Anders |chapter=What is Structural Biology and When Did It Start |pages=7–9 |chapter-url={{GBurl|aCvtLB0hX44C|p=7}} |title=Textbook of Structural Biology |date=2009 |publisher=World Scientific |isbn=978-981-277-207-7 }}

Early structural biologists throughout the 19th and early 20th centuries were primarily only able to study structures to the limit of the naked eye's visual acuity and through magnifying glasses and light microscopes. In the 20th century, a variety of experimental techniques were developed to examine the 3D structures of biological molecules. The most prominent techniques are X-ray crystallography, nuclear magnetic resonance, and electron microscopy. Through the discovery of X-rays and its applications to protein crystals, structural biology was revolutionized, as now scientists could obtain the three-dimensional structures of biological molecules in atomic detail.{{cite journal |last1=Curry |first1=Stephen |title=Structural Biology: A Century-long Journey into an Unseen World |journal=Interdisciplinary Science Reviews |date=3 July 2015 |volume=40 |issue=3 |pages=308–328 |doi=10.1179/0308018815Z.000000000120 |pmc=4697198 |pmid=26740732 |bibcode=2015ISRv...40..308C }} Likewise, NMR spectroscopy allowed information about protein structure and dynamics to be obtained.{{cite journal |last1=Campbell |first1=Iain D. |title=The evolution of protein NMR |journal=Biomedical Spectroscopy and Imaging |date=2013 |volume=2 |issue=4 |pages=245–264 |doi=10.3233/BSI-130055 |doi-access=free }} Finally, in the 21st century, electron microscopy also saw a drastic revolution with the development of more coherent electron sources, aberration correction for electron microscopes, and reconstruction software that enabled the successful implementation of high resolution cryo-electron microscopy, thereby permitting the study of individual proteins and molecular complexes in three-dimensions at angstrom resolution.

With the development of these three techniques, the field of structural biology expanded and also became a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules (especially proteins, made up of amino acids, RNA or DNA, made up of nucleotides, and membranes, made up of lipids), how they acquire the structures they have, and how alterations in their structures affect their function.{{cite book |last1=Banaszak |first1=Leonard J. |title=Foundations of Structural Biology |date=2000 |publisher=Elsevier |isbn=978-0-08-052184-8 }}{{pn|date=February 2025}} This subject is of great interest to biologists because macromolecules carry out most of the functions of cells, and it is only by coiling into specific three-dimensional shapes that they are able to perform these functions. This architecture, the "tertiary structure" of molecules, depends in a complicated way on each molecule's basic composition, or "primary structure." At lower resolutions, tools such as FIB-SEM tomography have allowed for greater understanding of cells and their organelles in 3-dimensions, and how each hierarchical level of various extracellular matrices contributes to function (for example in bone). In the past few years it has also become possible to predict highly accurate physical molecular models to complement the experimental study of biological structures. Computational techniques such as molecular dynamics simulations can be used in conjunction with empirical structure determination strategies to extend and study protein structure, conformation and function.{{cite journal |last1=Karplus |first1=Martin |last2=McCammon |first2=J. Andrew |title=Molecular dynamics simulations of biomolecules |journal=Nature Structural Biology |date=September 2002 |volume=9 |issue=9 |pages=646–652 |doi=10.1038/nsb0902-646 |pmid=12198485 }}File:Hemoglobin t-r state ani.gif, the oxygen transporting protein found in red blood cells]]

File:Protein structure examples.png (PDB)|alt=]]

History

In 1912 Max Von Laue directed X-rays at crystallized copper sulfate generating a diffraction pattern.{{cite journal | vauthors = Curry S | title = Structural Biology: A Century-long Journey into an Unseen World | journal = Interdisciplinary Science Reviews | volume = 40 | issue = 3 | pages = 308–328 | date = July 2015 | pmid = 26740732 | pmc = 4697198 | doi = 10.1179/0308018815z.000000000120 | bibcode = 2015ISRv...40..308C | doi-access = free }} These experiments led to the development of X-ray crystallography, and its usage in exploring biological structures.{{Cite journal |last1=Jumper |first1=John |last2=Evans |first2=Richard |last3=Pritzel |first3=Alexander |last4=Green |first4=Tim |last5=Figurnov |first5=Michael |last6=Ronneberger |first6=Olaf |last7=Tunyasuvunakool |first7=Kathryn |last8=Bates |first8=Russ |last9=Žídek |first9=Augustin |last10=Potapenko |first10=Anna |last11=Bridgland |first11=Alex |last12=Meyer |first12=Clemens |last13=Kohl |first13=Simon A. A. |last14=Ballard |first14=Andrew J. |last15=Cowie |first15=Andrew |date=2021-07-15 |title=Highly accurate protein structure prediction with AlphaFold |journal=Nature |language=en |volume=596 |issue=7873 |pages=583–589 |doi=10.1038/s41586-021-03819-2 |pmid=34265844 |pmc=8371605 |bibcode=2021Natur.596..583J |issn=1476-4687}} In 1951, Rosalind Franklin and Maurice Wilkins used X-ray diffraction patterns to capture the first image of deoxyribonucleic acid (DNA). Francis Crick and James Watson modeled the double helical structure of DNA using this same technique in 1953 and received the Nobel Prize in Medicine along with Wilkins in 1962.{{Cite web |title=The Nobel Prize in Physiology or Medicine 1962 |url=https://www.nobelprize.org/prizes/medicine/1962/summary/ |access-date=2022-10-01 |website=NobelPrize.org |language=en-US}}

Pepsin crystals were the first proteins to be crystallized for use in X-ray diffraction, by Theodore Svedberg who received the 1962 Nobel Prize in Chemistry.{{cite journal | vauthors = Jaskolski M, Dauter Z, Wlodawer A | title = A brief history of macromolecular crystallography, illustrated by a family tree and its Nobel fruits | journal = The FEBS Journal | volume = 281 | issue = 18 | pages = 3985–4009 | date = September 2014 | pmid = 24698025 | pmc = 6309182 | doi = 10.1111/febs.12796 }} The first tertiary protein structure, that of myoglobin, was published in 1958 by John Kendrew.{{cite journal | vauthors = Kendrew JC, Bodo G, Dintzis HM, Parrish RG, Wyckoff H, Phillips DC | title = A three-dimensional model of the myoglobin molecule obtained by x-ray analysis | journal = Nature | volume = 181 | issue = 4610 | pages = 662–666 | date = March 1958 | pmid = 13517261 | doi = 10.1038/181662a0 | bibcode = 1958Natur.181..662K | s2cid = 4162786 }} During this time, modeling of protein structures was done using balsa wood or wire models.{{cite journal | vauthors = Garman EF | title = Developments in x-ray crystallographic structure determination of biological macromolecules | journal = Science | volume = 343 | issue = 6175 | pages = 1102–1108 | date = March 2014 | pmid = 24604194 | doi = 10.1126/science.1247829 | bibcode = 2014Sci...343.1102G | s2cid = 21067016 }} With the invention of modeling software such as CCP4 in the late 1970s,{{Cite web|title=About CCP4|url=http://legacy.ccp4.ac.uk/about.php|access-date=2021-04-02|website=legacy.ccp4.ac.uk}} modeling is now done with computer assistance. Recent developments in the field have included the generation of X-ray free electron lasers, allowing analysis of the dynamics and motion of biological molecules,{{cite journal | vauthors = Waldrop MM | title = X-ray science: The big guns | journal = Nature | volume = 505 | issue = 7485 | pages = 604–606 | date = January 2014 | pmid = 24476872 | doi = 10.1038/505604a | bibcode = 2014Natur.505..604W | doi-access = free }} and the use of structural biology in assisting synthetic biology.{{cite journal | vauthors = Kiel C, Serrano L | title = Structural data in synthetic biology approaches for studying general design principles of cellular signaling networks | language = English | journal = Structure | volume = 20 | issue = 11 | pages = 1806–1813 | date = November 2012 | pmid = 23141693 | doi = 10.1016/j.str.2012.10.002 | doi-access = free | hdl = 10230/23121 | hdl-access = free }}

In the late 1930s and early 1940s, the combination of work done by Isidor Rabi, Felix Bloch, and Edward Mills Purcell led to the development of nuclear magnetic resonance (NMR). Currently, solid-state NMR is widely used in the field of structural biology to determine the structure and dynamic nature of proteins (protein NMR).{{cite journal | vauthors = Wüthrich K | title = The way to NMR structures of proteins | journal = Nature Structural Biology | volume = 8 | issue = 11 | pages = 923–925 | date = November 2001 | pmid = 11685234 | doi = 10.1038/nsb1101-923 | s2cid = 26153265 }}

In 1990, Richard Henderson produced the first three-dimensional, high resolution image of bacteriorhodopsin using cryogenic electron microscopy (cryo-EM).{{cite journal | vauthors = Henderson R, Baldwin JM, Ceska TA, Zemlin F, Beckmann E, Downing KH | title = Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy | journal = Journal of Molecular Biology | volume = 213 | issue = 4 | pages = 899–929 | date = June 1990 | pmid = 2359127 | doi = 10.1016/S0022-2836(05)80271-2 }} Since then, cryo-EM has emerged as an increasingly popular technique to determine three-dimensional, high resolution structures of biological images.{{Cite journal |last=Callaway |first=Ewen |date=2020-02-10 |title=Revolutionary cryo-EM is taking over structural biology |journal=Nature |language=en |volume=578 |issue=7794 |pages=201 |doi=10.1038/d41586-020-00341-9|pmid=32047310 |bibcode=2020Natur.578..201C |s2cid=211081167 |doi-access=free }}

More recently, computational methods have been developed to model and study biological structures. For example, molecular dynamics (MD) is commonly used to analyze the dynamic movements of biological molecules. In 1975, the first simulation of a biological folding process using MD was published in Nature.{{cite journal | vauthors = Levitt M, Warshel A | title = Computer simulation of protein folding | journal = Nature | volume = 253 | issue = 5494 | pages = 694–698 | date = February 1975 | pmid = 1167625 | doi = 10.1038/253694a0 | bibcode = 1975Natur.253..694L | s2cid = 4211714 }} Recently, protein structure prediction was significantly improved by a new machine learning method called AlphaFold.{{cite journal | vauthors = Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D | display-authors = 6 | title = Highly accurate protein structure prediction with AlphaFold | journal = Nature | volume = 596 | issue = 7873 | pages = 583–589 | date = August 2021 | pmid = 34265844 | pmc = 8371605 | doi = 10.1038/s41586-021-03819-2 | bibcode = 2021Natur.596..583J }} Some claim that computational approaches are starting to lead the field of structural biology research.{{Cite journal|last1=Nussinov|first1=Ruth|last2=Tsai|first2=Chung-Jung|last3=Shehu|first3=Amarda|last4=Jang|first4=Hyunbum|date=2019-02-12|title=Computational Structural Biology: Successes, Future Directions, and Challenges|journal=Molecules (Basel, Switzerland)|volume=24|issue=3|pages=E637|doi=10.3390/molecules24030637|issn=1420-3049|pmc=6384756|pmid=30759724|doi-access=free}}

Techniques

Biomolecules are too small to see in detail even with the most advanced light microscopes. The methods that structural biologists use to determine their structures generally involve measurements on vast numbers of identical molecules at the same time. These methods include:

Mass spectrometry
Macromolecular crystallography
Neutron diffraction
Proteolysis
Nuclear magnetic resonance spectroscopy of proteins (NMR)
Electron paramagnetic resonance (EPR)
Cryogenic electron microscopy (cryoEM)
Electron crystallography and microcrystal electron diffraction
Multiangle light scattering
Small angle scattering
Ultrafast laser spectroscopy
Anisotropic terahertz microspectroscopy
Two-dimensional infrared spectroscopy
Dual-polarization interferometry and circular dichroism

Most often researchers use them to study the "native states" of macromolecules. But variations on these methods are also used to watch nascent or denatured molecules assume or reassume their native states. See protein folding.

A third approach that structural biologists take to understanding structure is bioinformatics to look for patterns among the diverse sequences that give rise to particular shapes. Researchers often can deduce aspects of the structure of integral membrane proteins based on the membrane topology predicted by hydrophobicity analysis. See protein structure prediction.

Applications

File:Structural Biology and Drug Discovery.png

Structural biologists have made significant contributions towards understanding the molecular components and mechanisms underlying human diseases. For example, cryo-EM and ssNMR have been used to study the aggregation of amyloid fibrils, which are associated with Alzheimer's disease, Parkinson's disease, and type II diabetes.{{cite journal | vauthors = Iadanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE | title = A new era for understanding amyloid structures and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 19 | issue = 12 | pages = 755–773 | date = December 2018 | pmid = 30237470 | doi = 10.1038/s41580-018-0060-8 | s2cid = 52307956 | url = http://eprints.whiterose.ac.uk/136866/ }} In addition to amyloid proteins, scientists have used cryo-EM to produce high resolution models of tau filaments in the brain of Alzheimer's patients which may help develop better treatments in the future.{{Cite journal|last1=Fitzpatrick|first1=Anthony W. P.|last2=Falcon|first2=Benjamin|last3=He|first3=Shaoda|last4=Murzin|first4=Alexey G.|last5=Murshudov|first5=Garib|last6=Garringer|first6=Holly J.|last7=Crowther|first7=R. Anthony|last8=Ghetti|first8=Bernardino|last9=Goedert|first9=Michel|last10=Scheres|first10=Sjors H. W.|date=2017-07-13|title=Cryo-EM structures of tau filaments from Alzheimer's disease|journal=Nature|volume=547|issue=7662|pages=185–190|doi=10.1038/nature23002|issn=1476-4687|pmc=5552202|pmid=28678775|bibcode=2017Natur.547..185F}} Structural biology tools can also be used to explain interactions between pathogens and hosts. For example, structural biology tools have enabled virologists to understand how the HIV envelope allows the virus to evade human immune responses.{{Cite journal |last1=Engelman |first1=Alan |last2=Cherepanov |first2=Peter |date=2012-03-16 |title=The structural biology of HIV-1: mechanistic and therapeutic insights |journal=Nature Reviews Microbiology |volume=10 |issue=4 |pages=279–290 |doi=10.1038/nrmicro2747 |pmid=22421880 |pmc=3588166 |s2cid=14088805 |issn=1740-1526|doi-access=free }}

Structural biology is also an important component of drug discovery.{{cite journal | vauthors = Thomas SE, Mendes V, Kim SY, Malhotra S, Ochoa-Montaño B, Blaszczyk M, Blundell TL | title = Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections: A Paper Dedicated to John Kendrew | journal = Journal of Molecular Biology | volume = 429 | issue = 17 | pages = 2677–2693 | date = August 2017 | pmid = 28648615 | doi = 10.1016/j.jmb.2017.06.014 | series = John Kendrew’s 100th Anniversary Special Edition | doi-access = free }} Scientists can identify targets using genomics, study those targets using structural biology, and develop drugs that are suited for those targets. Specifically, ligand-NMR, mass spectrometry, and X-ray crystallography are commonly used techniques in the drug discovery process. For example, researchers have used structural biology to better understand Met, a protein encoded by a protooncogene that is an important drug target in cancer.{{cite journal|vauthors=Wendt KU, Weiss MS, Cramer P, Heinz DW|date=February 2008|title=Structures and diseases|journal=Nature Structural & Molecular Biology|volume=15|issue=2|pages=117–120|doi=10.1038/nsmb0208-117|pmc=7097323|pmid=18250627}} Similar research has been conducted for HIV targets to treat people with AIDS. Researchers are also developing new antimicrobials for mycobacterial infections using structure-driven drug discovery.

References

External links

{{Commons category-inline}}
[http://www.nature.com/nsmb/ Nature: Structural & Molecular Biology magazine website]
[http://www.journals.elsevier.com/journal-of-structural-biology/ Journal of Structural Biology]
[http://biochemweb.fenteany.com/structural.shtml Structural Biology - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology]
[http://www.structuralbiology.eu Structural Biology in Europe]
[https://www.xtal.iqf.csic.es/Cristalografia/index-en.html Learning Crystallography]

Category:Molecular biology

Category:Protein structure

Category:Biophysics