
Protein tertiary structure is the three dimensional shape of a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
. The tertiary structure will have a single
polypeptide chain "backbone" with one or more
protein secondary structures, the
protein domains.
Amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
side chains 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
Every atom is composed of a nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has no neutrons.
Every solid, liquid, gas ...
ic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure.
[Branden C. and Tooze J. "Introduction to Protein Structure" Garland Publishing, New York. 1990 and 1991.] A number of tertiary structures may fold into a
quaternary structure.
[Kyte, J. "Structure in Protein Chemistry." Garland Publishing, New York. 1995. ]
History
The science of the tertiary structure of proteins has progressed from one of
hypothesis
A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can testable, test it. Scientists generally base scientific hypotheses on prev ...
to one of detailed definition. Although
Emil Fischer had suggested proteins were made of
polypeptide chains and amino acid side chains, it was
Dorothy Maud Wrinch who incorporated
geometry
Geometry (; ) is, with arithmetic, one of the oldest branches of mathematics. It is concerned with properties of space such as the distance, shape, size, and relative position of figures. A mathematician who works in the field of geometry is c ...
into the prediction of
protein structure
Protein structure is the molecular geometry, three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single ami ...
s. Wrinch demonstrated this with the
''Cyclol'' model, the first prediction of the structure of a
globular protein. Contemporary methods are able to determine, without prediction, tertiary structures to within 5
Å (0.5 nm) for small proteins (<120 residues) and, under favorable conditions, confident
secondary structure predictions.
Determinants
Stability of native states
Thermostability
A protein folded into its
native state or
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
cellular environment. Because many similar conformations will have similar energies, protein structures are
dynamic, fluctuating between these similar structures.
Globular proteins have a core of
hydrophobic amino acid residues and a surface region of
water
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as ...
-exposed, charged,
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are ...
residues. This arrangement may stabilise interactions within the tertiary structure. For example, in
secreted proteins, which are not bathed in
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
,
disulfide bonds 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
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
. For example, the
TIM barrel, named for the enzyme
triosephosphateisomerase, is a common tertiary structure as is the highly stable,
dimeric,
coiled coil structure. Hence, proteins may be classified by the structures they hold. Databases of proteins which use such a classification include ''
SCOP
A (
or ) was a poet as represented in Old English literature#Poetry, Old English poetry. The scop is the Old English counterpart of the Old Norse ', with the important difference that "skald" was applied to historical persons, and scop is used ...
'' and ''
CATH
The CATH Protein Structure Classification database is a free, publicly available online resource that provides information on the evolutionary relationships of protein domains. It was created in the mid-1990s by Professor Christine Orengo and coll ...
''.
Kinetic traps
Folding
kinetics
Kinetics ( grc, κίνησις, , kinesis, ''movement'' or ''to move'') may refer to:
Science and medicine
* Kinetics (physics), the study of motion and its causes
** Rigid body kinetics, the study of the motion of rigid bodies
* Chemical k ...
may trap a protein in a high-
energy
In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of hea ...
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
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
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
.
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
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
.
Chaperone proteins
It is commonly assumed that the native state of a protein is also the most
thermodynamically stable and that a protein will reach its native state, given its
chemical kinetics
Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is to be contrasted with chemical thermodynamics, which deals with the direction in ...
, before it is
translated. 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
homologous
Homology may refer to:
Sciences
Biology
*Homology (biology), any characteristic of biological organisms that is derived from a common ancestor
*Sequence homology, biological homology between DNA, RNA, or protein sequences
* Homologous chrom ...
eukaryotic heat shock proteins (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
The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, c ...
s. This only takes into account the cytoplasmic environment present at the time of
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, for example an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
, may change upon binding of its natural ligands, for example a
cofactor. In this case, the structure of the protein bound to the ligand is known as holo structure, of the unbound protein as apo structure.
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 proteins is more advanced than that of
membrane proteins because the former are easier to study with available technology.
X-ray crystallography
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...
is the most common tool used to determine
protein structure
Protein structure is the molecular geometry, three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single ami ...
. It provides high resolution of the structure but it does not give information about protein's
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
symmetrical complexes of
protein subunits.
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
Stanford University is a
distributed computing research effort which uses approximately 5
petaFLOPS (≈10 x86 petaFLOPS) of available computing. It aims to find an
algorithm
In mathematics and computer science, an algorithm () is a finite sequence of rigorous instructions, typically used to solve a class of specific problems or to perform a computation. Algorithms are used as specifications for performing ...
which will consistently predict protein tertiary and quaternary structures given the protein's amino acid sequence and its cellular conditions.
["Folding@home."](_blank)
Stanford University. Accessed 18 December 2013.["Folding@home – FAQ"](_blank)
Stanford University. Accessed 18 December 2013.["Folding@home – Science."](_blank)
Stanford University.
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
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
and
prion
Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...
diseases such as
bovine spongiform encephalopathy can be better understood by constructing (and reconstructing)
disease models. 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 manipulation.
Protein structure prediction is a new way to create disease models, which may avoid the use of animals.
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.
See also
*
Folding (chemistry)
*
I-TASSER
*
Nucleic acid tertiary structure
*
Protein contact map
*
Proteopedia
*
Structural biology
*
Structural motif
*
Protein tandem repeats
References
External links
Protein Data BankDisplay, analyse and superimpose protein 3D structuresDisplay, analyse and superimpose protein 3D structuresWWW-based course teaching elementary protein bioinformaticsCritical Assessment of Structure Prediction (CASP)Structural Classification of Proteins (SCOP)CATH Protein Structure ClassificationDALI/FSSP software and database of superposed protein structuresTOPOFIT-DB Invariant Structural Cores between proteins*
PDBWiki PDBWiki was a wiki that functioned as a user-contributed database of protein structure annotations, listing all the protein structures available in the Protein Data Bank (PDB). It ran on the MediaWiki wiki application from 2007 to 2013. The website ...
�
PDBWiki Home Page– a website for community annotation of PDB structures.
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