View source for 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">{{cite book |last1=Brändén |first1=Carl-Ivar |last2=Tooze |first2=John |title=Introduction to protein structure |date=1999 |publisher=Garland Science |location=New York |isbn=978-0-8153-2305-1 |edition=2nd}}</ref> A number of these structures may bind to each other, forming a [[Protein quaternary structure|quaternary structure]].<ref name=kyte>{{cite book |last1=Kyte |first1=Jack |title=Structure in protein chemistry |date=1995 |publisher=Garland Pub |location=New York |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>{{cite book |last1=Senechal |first1=Marjorie |title=I Died for Beauty: Dorothy Wrinch and the Cultures of Science |date=2012 |publisher=Oxford University Press |location=New York |isbn=0-19-991083-9 |chapter=The Cyclol Model |url=https://books.google.com/books?id=KE0k-reQCP8C&q=dorothy+wrinch}}</ref> Under favorable conditions, such as confident knowledge of [[secondary structure]], contemporary methods are sometimes able to predict the tertiary structure of small proteins (<120 residues) ''de novo'' to within 5 [[Angstrom|Å]] (0.5&nbsp;nm).{{Citation needed|date=February 2007}}{{Update inline|date=October 2025|reason=Requires updating given the progress in [[protein structure prediction]] over the last 20 years}}

== Determinants ==
{{Main article|Protein folding}}

=== Stability of native states ===
{{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]]''.

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]].

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 |last1=Whisstock |first1=James C |last2=Bottomley |first2=Stephen P |title=Molecular gymnastics: serpin structure, folding and misfolding |journal=Current Opinion in Structural Biology |date=December 2006 |volume=16 |issue=6 |pages=761–768 |doi=10.1016/j.sbi.2006.10.005 | pmid = 17079131}}</ref><ref>{{cite journal |last1=Gettins |first1=Peter G. W. |title=Serpin Structure, Mechanism, and Function |journal=Chemical Reviews |date=1 December 2002 |volume=102 |issue=12 |pages=4751–4804 |doi=10.1021/cr010170 |pmid=12475206}}</ref><ref>{{cite journal |last1=Whisstock |first1=James C |last2=Skinner |first2=Richard |last3=Carrell |first3=Robin W |last4=Lesk |first4=Arthur M |title=Conformational changes in serpins: I. the native and cleaved conformations of α 1 -antitrypsin 1 1Edited by J. M. Thornton |journal=Journal of Molecular Biology |date=February 2000 |volume=296 |issue=2 |pages=685–699 |doi=10.1006/jmbi.1999.3520 |pmid=10669617}}</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 |last1=Seeliger |first1=Daniel |last2=de Groot |first2=Bert L. |title=Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations |journal=PLoS Computational Biology |date=8 January 2010 |volume=6 |issue=1 |article-number=e1000634 |doi=10.1371/journal.pcbi.1000634 |pmid=20066034|pmc=2796265|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.

=== 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]].

== 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]]