Editing Binding site (section)

== Types ==

=== Active site ===
{{Main|Active site}}
At the active site, a substrate binds to an enzyme to induce a chemical reaction.<ref name=":3">{{cite book | vauthors = Wilson K |chapter=Enzymes|date=March 2010|chapter-url=https://www.cambridge.org/core/books/principles-and-techniques-of-biochemistry-and-molecular-biology/enzymes/10382334B13C92480C86AA1E10F9DABD|pages=581–624|publisher=Cambridge University Press|language=en|doi=10.1017/cbo9780511841477.016|isbn=9780511841477|access-date=2018-11-01|title=Principles and Techniques of Biochemistry and Molecular Biology| veditors = Wilson K, Walker J }}</ref><ref>{{Cite book|title=Dictionary of Chemical Engineering| vauthors = Schaschke C |publisher=Oxford University Press|year=2014|isbn=978-1-62870-844-8}}</ref> Substrates, transition states, and products can bind to the active site, as well as any competitive inhibitors.<ref name=":3" /> For example, in the context of protein function, the binding of calcium to troponin in muscle cells can induce a conformational change in troponin. This allows for tropomyosin to expose the actin-myosin binding site to which the myosin head binds to form a [[Sliding filament theory|cross-bridge]] and induce a [[muscle contraction]].<ref>{{Cite book|title=Biology How Life Works| vauthors = Morris J | publisher= W.H. Freeman and Company|year=2016|isbn=978-1-4641-2609-3|location=United States of America|pages=787–792}}</ref>

In the context of the blood, an example of competitive binding is carbon monoxide which competes with oxygen for the active site on [[heme]]. Carbon monoxide's high affinity may outcompete oxygen in the presence of low oxygen concentration. In these circumstances, the binding of carbon monoxide induces a conformation change that discourages heme from binding to oxygen, resulting in carbon monoxide poisoning.<ref name="Hardin_2013" />
[[File:Enzyme inhibition.png|thumb|Competitive and noncompetitive enzyme binding at active and regulatory (allosteric) site respectively.]]

=== Allosteric site ===
At the regulatory site, the binding of a ligand may elicit amplified or inhibited protein function.<ref name="Hardin_2013" /><ref name="Konc_2014">{{cite journal | vauthors = Konc J, Janežič D | title = Binding site comparison for function prediction and pharmaceutical discovery | journal = Current Opinion in Structural Biology | volume = 25 | pages = 34–9 | date = April 2014 | pmid = 24878342 | doi = 10.1016/j.sbi.2013.11.012 }}</ref> The binding of a ligand to an allosteric site of a multimeric enzyme often induces positive cooperativity, that is the binding of one substrate induces a favorable conformation change and increases the enzyme's likelihood to bind to a second substrate.<ref name = "Fuqua_2004">{{cite book | vauthors = Fuqua C, White D |chapter=Prokaryotic Intercellular Signalling |date=2004 |title=Cell Signalling in Prokaryotes and Lower Metazoa |pages=27–71 |publisher=Springer Netherlands |isbn=9789048164837 | doi = 10.1007/978-94-017-0998-9_2}}</ref> Regulatory site ligands can involve [[Allosteric regulation#Types|homotropic]] and [[Allosteric regulation#Types|heterotropic]] ligands, in which single or multiple types of molecule affects enzyme activity respectively.<ref name="Creighton_2010">{{cite book|title=The Biophysical Chemistry of Nucleic Acids & Proteins| vauthors = Creighton TE |date=2010|publisher=Helvetian Press |isbn=978-0956478115|oclc=760830351}}</ref>

Enzymes that are highly regulated are often essential in metabolic pathways. For example, [[phosphofructokinase]] (PFK), which phosphorylates fructose in glycolysis, is largely regulated by ATP. Its regulation in glycolysis is imperative because it is the committing and rate limiting step of the pathway. PFK also controls the amount of glucose designated to form ATP through the [[Catabolism|catabolic]] pathway. Therefore, at sufficient levels of ATP, PFK is allosterically inhibited by ATP. This regulation efficiently conserves glucose reserves, which may be needed for other pathways. Citrate, an intermediate of the citric acid cycle, also works as an allosteric regulator of PFK.<ref name="Creighton_2010" /><ref name = "Currell_1997">{{Cite book | vauthors = Currell BR, van Dam-Mieras MC |title=Biotechnological Innovations in Chemical Synthesis |publisher= Butterworth-Heinemann |location=Oxford |year=1997 |isbn=978-0-7506-0561-8 |pages=125–128 }}</ref>

=== Single- and multi-chain binding sites ===
Binding sites can be characterized also by their structural features. Single-chain sites (of “monodesmic” ligands, μόνος: single, δεσμός: binding) are formed by a single protein chain, while multi-chain sites (of "polydesmic” ligands, πολοί: many)<ref name="pmid31306664">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand Binding Site Structure Shapes Folding, Assembly and Degradation of Homomeric Protein Complexes. | journal = Journal of Molecular Biology | volume = 431 | issue = 19 | pages = 3871–3888 | date = 2019 | pmid = 31306664 | pmc = 6739599 | doi = 10.1016/j.jmb.2019.07.014 }}</ref> are frequent in protein complexes, and are formed by ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that binding site structure has profound consequences for the biology of protein complexes (evolution of function, allostery).<ref name="pmid29562182">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology. | journal = Cell Reports | volume = 22 | issue = 12 | pages = 3265–3276 | date = 2018 | pmid = 29562182 | pmc = 5873459 | doi = 10.1016/j.celrep.2018.02.085 }}</ref><ref name="pmid31004156">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes. | journal = Molecular Biology and Evolution | volume = 36 | issue = 8 | pages = 1711–1727 | date = 2019 | pmid = 31004156 | pmc = 6657754 | doi = 10.1093/molbev/msz093 }}</ref>

=== Cryptic binding sites ===
Cryptic binding sites are the binding sites that are transiently formed in an apo form or that are induced by ligand binding. Considering the cryptic binding sites increases the size of the potentially “[[Druggability|druggable]]” human proteome from ~40% to ~78% of disease-associated proteins.<ref name=":1">{{cite journal | vauthors = Cimermancic P, Weinkam P, Rettenmaier TJ, Bichmann L, Keedy DA, Woldeyes RA, Schneidman-Duhovny D, Demerdash ON, Mitchell JC, Wells JA, Fraser JS, Sali A | display-authors = 6 | title = CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites | journal = Journal of Molecular Biology | volume = 428 | issue = 4 | pages = 709–719 | date = February 2016 | pmid = 26854760 | doi = 10.1016/j.jmb.2016.01.029 | pmc = 4794384 | doi-access = free }}</ref> The binding sites have been investigated by: [[Support-vector machine|support vector machine]] applied to "CryptoSite" data set,<ref name=":1" /> Extension of "CryptoSite" data set,<ref>{{cite journal | vauthors = Beglov D, Hall DR, Wakefield AE, Luo L, Allen KN, Kozakov D, Whitty A, Vajda S | display-authors = 6 | title = Exploring the structural origins of cryptic sites on proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 15 | pages = E3416–E3425 | date = April 2018 | pmid = 29581267 | doi = 10.1073/pnas.1711490115 | pmc = 5899430 | bibcode = 2018PNAS..115E3416B | doi-access = free }}</ref> long timescale [[Molecular dynamics|molecular dynamics simulation]] with Markov state model and with biophysical experiments,<ref>{{cite journal | vauthors = Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S | title = Discovery of multiple hidden allosteric sites by combining Markov state models and experiments | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 9 | pages = 2734–9 | date = March 2015 | pmid = 25730859 | pmc = 4352775 | doi = 10.1073/pnas.1417811112 | bibcode = 2015PNAS..112.2734B | doi-access = free }}</ref> and cryptic-site index that is based on relative [[accessible surface area]].<ref>{{cite journal | vauthors = Iida S, Nakamura HK, Mashimo T, Fukunishi Y | title = Structural Fluctuations of Aromatic Residues in an Apo-Form Reveal Cryptic Binding Sites: Implications for Fragment-Based Drug Design | journal = The Journal of Physical Chemistry B | volume = 124 | issue = 45 | pages = 9977–9986 | date = November 2020 | pmid = 33140952 | doi = 10.1021/acs.jpcb.0c04963 | s2cid = 226244554 }}</ref>