Editing Protein tertiary structure

{{short description|Three dimensional shape of a protein}}
{{about|tertiary structure in protein|the article about tertiary structure in nucleic acid|Nucleic acid tertiary structure}}

{{refimprove|date=February 2025}}
{{Protein structure}}
[[File:Tertiary Structure of a Protein.svg|alt=Tertiary Structure of a Protein|frame|The tertiary structure of a protein consists of the way a polypeptide is formed of a complex molecular shape. This is caused by R-group interactions such as ionic and hydrogen bonds, disulphide bridges, and hydrophobic & hydrophilic interactions.]]
'''Protein tertiary structure''' is the three-dimensional shape of a [[protein]]. The tertiary structure will have a single [[polypeptide]] chain "backbone" with one or more [[protein secondary structure]]s, the [[protein domain]]s. [[Amino acid]] [[side chain]]s and the backbone may interact and bond in a number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its [[atom]]ic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure.<ref>{{GoldBookRef|title=tertiary structure|file=T06282}}</ref><ref name="bran">Branden C. and Tooze J. "Introduction to Protein Structure" Garland Publishing, New York. 1990 and 1991.</ref> A number of these structures may bind to each other, forming a [[Protein quaternary structure|quaternary structure]].<ref name=kyte>Kyte, J. "Structure in Protein Chemistry." Garland Publishing, New York. 1995. {{ISBN|0-8153-1701-8}}</ref>

== History ==
The science of the tertiary structure of proteins has progressed from one of [[hypothesis]] to one of detailed definition. Although [[Hermann Emil Fischer|Emil Fischer]] had suggested proteins were made of [[polypeptide chain]]s and amino acid side chains, it was [[Dorothy Maud Wrinch]] who incorporated [[geometry]] into the prediction of [[protein structure]]s. Wrinch demonstrated this with the [[Cyclol|''Cyclol'' model]], the first prediction of the structure of a [[globular protein]].<ref>Senechal M. [https://books.google.com/books?id=KE0k-reQCP8C&q=dorothy+wrinch "I died for beauty: Dorothy Wrinch and the cultures of science."] Oxford University Press, 2012. Chapter 14. {{ISBN|0-19-991083-9}}, 9780199910830. Accessed at Google Books 8 December 2013.</ref> Contemporary methods are able to determine, without prediction, tertiary structures to within 5 [[Angstrom|Å]] (0.5&nbsp;nm) for small proteins (<120 residues) and, under favorable conditions, confident [[secondary structure]] predictions.
== Determinants ==
{{Main article|Protein folding}}

=== Stability of native states ===

==== Thermostability ====
{{See also|Equilibrium unfolding}}
A protein folded into its [[native state]] or [[chemical conformation|native conformation]] typically has a lower [[Gibbs free energy]] (a combination of [[enthalpy]] and [[entropy]]) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the [[cell (biology)|cellular]] environment. Because many similar conformations will have similar energies, protein structures are [[Protein dynamics|dynamic]], fluctuating between these similar structures.

[[Globular protein]]s have a core of [[hydrophobic]] amino acid residues and a surface region of [[water]]-exposed, charged, [[hydrophilic]] residues. This arrangement may stabilize interactions within the tertiary structure. For example, in [[secrete]]d proteins, which are not bathed in [[cytoplasm]], [[disulfide bond]]s between [[cysteine]] residues help to maintain the tertiary structure. There is a commonality of stable tertiary structures seen in proteins of diverse function and diverse [[molecular evolution|evolution]]. For example, the [[TIM barrel]], named for the enzyme [[triosephosphateisomerase]], is a common tertiary structure as is the highly stable, [[dimer (chemistry)|dimeric]], [[coiled coil]] structure. Hence, proteins may be  classified by the structures they hold. Databases of proteins which use such a classification include ''[[Structural Classification of Proteins|SCOP]]'' and ''[[CATH]]''.

==== Kinetic traps ====
Folding [[Chemical kinetics|kinetics]] may trap a protein in a high-[[energy]] conformation, i.e. a high-energy intermediate conformation blocks access to the lowest-energy conformation. The high-energy conformation may contribute to the function of the protein. For example, the [[influenza]] [[hemagglutinin]] protein is a single polypeptide chain which when activated, is [[proteolysis|proteolytically]] cleaved to form two polypeptide chains. The two chains are held in a high-energy conformation. When the local [[pH]] drops, the protein undergoes an energetically favorable conformational rearrangement that enables it to penetrate the host [[cell membrane]].

==== Metastability ====
Some tertiary protein structures may exist in long-lived states that are not the expected most stable state. For example, many [[serpins]] (serine protease inhibitors) show this [[metastability]]. They undergo a [[conformational change]] when a loop of the protein is cut by a [[protease]].<ref name="whis">{{cite journal | author = Whisstock J | year = 2006 | title = Molecular gymnastics: serpiginous structure, folding and scaffolding | journal = Current Opinion in Structural Biology | volume = 16 | issue = 6| pages = 761–68 | pmid = 17079131 | doi=10.1016/j.sbi.2006.10.005}}</ref><ref>{{cite journal |author=Gettins PG |title=Serpin structure, mechanism, and function |journal=Chem Rev |volume=102 |issue=12 |pages=4751–804 |year=2002 |pmid=12475206 |doi=10.1021/cr010170 }}</ref><ref>{{cite journal |vauthors=Whisstock JC, Skinner R, Carrell RW, Lesk AM |title=Conformational changes in serpins: I. The native and cleaved conformations of alpha(1)-anti-trypsin |pmid=10669617|journal=J Mol Biol |year=2000 |volume=296  |pages=685–99 |doi=10.1006/jmbi.1999.3520 |issue=2}}</ref>

=== Chaperone proteins ===
It is commonly assumed that the native state of a protein is also the most [[thermodynamics|thermodynamically]] stable and that a protein will reach its native state, given its [[chemical kinetics]], before it is [[translation (genetics)|translated]]. Protein [[chaperone (protein)|chaperones]] within the cytoplasm of a cell assist a newly synthesised polypeptide to attain its native state. Some chaperone proteins are highly specific in their function, for example, [[protein disulfide isomerase]]; others are general in their function and may assist most globular proteins, for example, the [[prokaryotic]] [[GroEL]]/[[GroES]] system of proteins and the [[homology (biology)|homologous]] [[eukaryotic]] [[heat shock protein]]s (the Hsp60/Hsp10 system).

=== Cytoplasmic environment ===
Prediction of protein tertiary structure relies on knowing the protein's [[primary structure]] and comparing the possible predicted tertiary structure with known tertiary structures in [[protein data bank]]s. This only takes into account the cytoplasmic environment present at the time of [[protein biosynthesis|protein synthesis]] to the extent that a similar cytoplasmic environment may also have influenced the structure of the proteins recorded in the protein data bank.

=== Ligand binding ===
The structure of a protein, such as an [[enzyme]], may change upon binding of its natural ligands, for example a [[Cofactor (biochemistry)|cofactor]]. In this case, the structure of the protein bound to the ligand is known as holo structure,  while the unbound protein has an apo structure.<ref>{{cite journal|pmid=20066034|pmc=2796265|year=2010|last1=Seeliger|first1=D|title=Conformational transitions upon ligand binding: Holo-structure prediction from apo conformations|journal=PLOS Computational Biology|volume=6|issue=1|page=e1000634|last2=De Groot|first2=B. L.|doi=10.1371/journal.pcbi.1000634|bibcode=2010PLSCB...6E0634S |doi-access=free }}</ref>

Structure stabilized by the formation of weak bonds between amino acid side chains
- Determined by the folding of the polypeptide chain on itself (nonpolar residues are located
inside the protein, while polar residues are mainly located outside)
- Envelopment of the protein brings the protein closer and relates a-to located in distant regions of the sequence
- Acquisition of the tertiary structure leads to the formation of pockets and sites suitable for the recognition and
the binding of specific molecules (biospecificity).

== Determination ==
The knowledge of the tertiary structure of soluble [[globular protein]]s is more advanced than that of [[membrane protein]]s because the former are easier to study with available technology.

=== X-ray crystallography ===
[[X-ray crystallography]] is the most common tool used to determine [[protein structure]]. It provides high resolution of the structure but it does not give information about protein's [[Protein dynamics|conformational flexibility]].

=== NMR ===
[[Protein NMR]] gives comparatively lower resolution of protein structure. It is limited to smaller proteins. However, it can provide information about conformational changes of a protein in solution.

=== Cryogenic electron microscopy ===
[[Cryogenic electron microscopy]] (cryo-EM) can give information about both a protein's tertiary and quaternary structure. It is particularly well-suited to large proteins and [[Protein complex|symmetrical complexes]] of [[protein subunit]]s.

=== Dual polarisation interferometry ===
[[Dual polarisation interferometry]] provides complementary information about surface captured proteins. It assists in determining structure and conformation changes over time.

== Projects ==

=== Prediction algorithm ===
The [[Folding@home]] project at the [[University of Pennsylvania]] is a [[distributed computing]] research effort which uses approximately 5 [[petaFLOPS]] (≈10 x86 petaFLOPS) of available computing. It aims to find an [[algorithm]] which will consistently predict protein tertiary and quaternary structures given the protein's amino acid sequence and its cellular conditions.<ref>{{Cite web |title=Folding@home – Fighting disease with a world wide distributed super computer. |url=https://foldingathome.org/ |access-date=2024-04-23 |language=en-US}}</ref><ref>{{Cite web |title=Bowman Lab – University of Pennsylvania |url=https://bowmanlab.seas.upenn.edu/ |access-date=2024-04-23 |language=en-US}}</ref>

A list of software for protein tertiary structure prediction can be found at
[[List of protein structure prediction software]].

=== Protein aggregation diseases ===
[[Protein aggregation]] diseases such as [[Alzheimer's disease]] and [[Huntington's disease]] and [[prion]] diseases such as [[bovine spongiform encephalopathy]] can be better understood by constructing (and reconstructing) [[disease model]]s. This is done by causing the disease in laboratory animals, for example, by administering a [[toxin]], such as [[MPTP]] to cause Parkinson's disease, or through [[genetic engineering|genetic manipulation]].<ref name="park">{{cite journal|title=Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP|pmid=15503155|doi=10.1007/s00441-004-0938-y | volume=318|issue=1|date=October 2004|journal=Cell Tissue Res.|pages=215–24|author=Schober A|s2cid=1824912}}</ref><ref name="ko">{{cite web|url=http://www.sigmaaldrich.com/catalog/genes/TP53|title=Tp53 Knockout Rat|publisher=Cancer|access-date=2010-12-18}}</ref>
[[Protein structure prediction]] is a new way to create disease models, which may avoid the use of animals.<ref name="bit">{{cite web|url=http://www.bit-tech.net/hardware/graphics/2009/06/15/what-is-folding-and-why-does-it-matter/|title=Feature – What is Folding and Why Does it Matter?|access-date=December 18, 2010|archive-url=https://web.archive.org/web/20131212083942/http://www.bit-tech.net/hardware/graphics/2009/06/15/what-is-folding-and-why-does-it-matter/|archive-date=December 12, 2013|url-status=dead}}</ref>

===Protein Tertiary Structure Retrieval Project (CoMOGrad)===

Matching patterns in tertiary structure of a given protein to huge number of known protein tertiary structures and retrieve most similar ones in ranked order is in the heart of many research areas like function prediction of novel proteins, study of evolution, disease diagnosis, drug discovery, antibody design etc. The CoMOGrad project at BUET is a research effort to device an extremely fast and much precise method for protein tertiary structure retrieval and develop online tool based on research outcome.<ref>{{Cite web | url=http://research.buet.ac.bd:8080/Comograd/ |title = Comograd :: Protein Tertiary Matching}}</ref><ref>{{cite journal |last1=Karim |first1=Rezaul |last2=Aziz |first2=Mohd Momin Al |last3=Shatabda |first3=Swakkhar |last4=Rahman |first4=M. Sohel |last5=Mia |first5=Md Abul Kashem |last6=Zaman |first6=Farhana |last7=Rakin |first7=Salman |title=CoMOGrad and PHOG: From Computer Vision to Fast and Accurate Protein Tertiary Structure Retrieval |journal=Scientific Reports |date=21 August 2015 |volume=5 |issue=1 |pages=13275 |doi=10.1038/srep13275 |pmid=26293226 |pmc=4543952 |arxiv=1409.0814 |bibcode=2015NatSR...513275K }}</ref>

== See also ==
{{colbegin}}
* [[Folding (chemistry)]]
* [[I-TASSER]]
* [[Nucleic acid tertiary structure]]
* [[Protein contact map]]
* [[Proteopedia]]
* [[Structural biology]]
* [[Structural motif]]
* [[Protein tandem repeats]]
{{colend}}

==References==
{{Reflist}}

== External links ==
* [https://web.archive.org/web/20150407064348/http://www.pdb.org/ Protein Data Bank]
* [http://ca.expasy.org/spdbv/ Display, analyse and superimpose protein 3D structures]
* [http://www.bioch.ox.ac.uk/howarth/alphabet.htm Alphabet of protein structures.]
* [http://swift.cmbi.ru.nl/whatif/ Display, analyse and superimpose protein 3D structures]
* [https://web.archive.org/web/20110718132234/http://swift.cmbi.ru.nl/teach/B1/ WWW-based course teaching elementary protein bioinformatics]
* [https://predictioncenter.org/ Critical Assessment of Structure Prediction (CASP)]
* [https://web.archive.org/web/20070911012207/http://scop.mrc-lmb.cam.ac.uk/scop/ Structural Classification of Proteins (SCOP)]
* [http://www.cathdb.info/ CATH Protein Structure Classification]
* [https://web.archive.org/web/20051125045348/http://ekhidna.biocenter.helsinki.fi/dali/start DALI/FSSP software and database of superposed protein structures]
* [https://web.archive.org/web/20081215084435/http://mozart.bio.neu.edu/topofit/index.php TOPOFIT-DB Invariant Structural Cores between proteins]
* [[PDBWiki]] — [http://pdbwiki.org/ PDBWiki Home Page] – a website for community annotation of PDB structures.

{{Protein tertiary structure}}
{{Biomolecular structure}}

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[[Category:Protein structure|Protein structure 3]]