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Binding site

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351: 31: 131: 217: 324:. This means that the binding of oxygen to a heme group on hemoglobin induces a favorable conformation change that allows for increased binding favorability of oxygen for the next heme groups. In these circumstances, the binding curve of hemoglobin will be sigmoidal due to its increased binding favorability for oxygen. Since myoglobin has only one heme group, it exhibits noncooperative binding which is hyperbolic on a binding curve. 413:
such as binding site are conserved. Structure based methods require the 3D structure of the protein. These methods in turn can be subdivided into template and pocket based methods. Template based methods search for 3D similarities between the target protein and proteins with known binding sites. The pocket based methods search for concave surfaces or buried pockets in the target protein that possess features such as
293: 347:, destroying the development of the bacterial cell wall and inducing cell death. Thus, the study of binding sites is relevant to many fields of research, including cancer mechanisms, drug formulation, and physiological regulation. The formulation of an inhibitor to mute a protein's function is a common form of pharmaceutical therapy. 412:
A number of computational tools have been developed for the prediction of the location of binding sites on proteins. These can be broadly classified into sequence based or structure based. Sequence based methods rely on the assumption that the sequences of functionally conserved portions of proteins
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At the regulatory site, the binding of a ligand may elicit amplified or inhibited protein function. 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
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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) are frequent in protein complexes, and are formed by
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or noncooperative binding behavior respectively. Typically, the x-axis describes the concentration of ligand and the y-axis describes the fractional saturation of ligands bound to all available binding sites. The Michaelis Menten equation is usually used when determining the shape of the curve. The
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For instance, the transferase hexokinase catalyzes the phosphorylation of glucose to make glucose-6-phosphate. Active site residues of hexokinase allow for stabilization of the glucose molecule in the active site and spur the onset of an alternative pathway of favorable interactions, decreasing the
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than substrates and products. At the catalytic binding site, several different interactions may act upon the substrate. These range from electric catalysis, acid and base catalysis, covalent catalysis, and metal ion catalysis. These interactions decrease the activation energy of a chemical reaction
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At the active site, a substrate binds to an enzyme to induce a chemical reaction. Substrates, transition states, and products can bind to the active site, as well as any competitive inhibitors. For example, in the context of protein function, the binding of calcium to troponin in muscle cells can
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Lastly, mixed inhibitors are able to bind to both the free enzyme and the enzyme-substrate complex. However, in contrast to competitive and uncompetitive inhibitors, mixed inhibitors bind to the allosteric site. Allosteric binding induces conformational changes that may increase the protein's
393:(β-Blockers) are antihypertensive agents that block the binding of the hormones adrenaline and noradrenaline to β1 and β2 receptors in the heart and blood vessels. These receptors normally mediate the sympathetic "fight or flight" response, causing constriction of the blood vessels. 249:
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.
213:. 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. 167:
compete with substrate to bind to free enzymes at active sites and thus impede the production of the enzyme-substrate complex upon binding. For example, carbon monoxide poisoning is caused by the competitive binding of carbon monoxide as opposed to oxygen in hemoglobin.
245:(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 2162:
Broomhead NK, Soliman ME (March 2017). "Can We Rely on Computational Predictions To Correctly Identify Ligand Binding Sites on Novel Protein Drug Targets? Assessment of Binding Site Prediction Methods and a Protocol for Validation of Predicted Binding Sites".
174:, alternatively, bind concurrently with substrate at active sites. Upon binding to an enzyme substrate (ES) complex, an enzyme substrate inhibitor (ESI) complex is formed. Similar to competitive inhibitors, the rate at product formation is decreased also. 309:
Michaelis Menten equation is derived based on steady-state conditions and accounts for the enzyme reactions taking place in a solution. However, when the reaction takes place while the enzyme is bound to a substrate, the kinetics play out differently.
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capacity that would allow them to bind ligands with high affinity. Even though the term pocket is used here, similar methods can be used to predict binding sites used in protein-protein interactions that are usually more planar, not in pockets.
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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).
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by providing favorable interactions to stabilize the high energy molecule. Enzyme binding allows for closer proximity and exclusion of substances irrelevant to the reaction. Side reactions are also discouraged by this specific binding.
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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
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Iida S, Nakamura HK, Mashimo T, Fukunishi Y (November 2020). "Structural Fluctuations of Aromatic Residues in an Apo-Form Reveal Cryptic Binding Sites: Implications for Fragment-Based Drug Design".
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Binding of a ligand to a binding site on protein often triggers a change in conformation in the protein and results in altered cellular function. Hence binding site on protein are critical parts of
122:, steric shape and geometry of the site selectively allow for highly specific ligands to bind, activating a particular cascade of cellular interactions the protein is responsible for. 404:
that causes flaccid paralysis in the muscle due to binding to acetylcholine dependent nerves. This interaction inhibits muscle contractions, giving the appearance of smooth muscle.
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affinity for substrate. This phenomenon is called positive modulation. Conversely, allosteric binding that decreases the protein's affinity for substrate is negative modulation.
1072: 118:. Binding sites incur functional changes in a number of contexts, including enzyme catalysis, molecular pathway signaling, homeostatic regulation, and physiological function. 1699:
Anne A, Demaille C (October 2012). "Kinetics of enzyme action on surface-attached substrates: a practical guide to progress curve analysis in any kinetic situation".
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Nazem, Fatemeh; Ghasemi, Fahimeh; Fassihi, Afshin; Mehri Dehnavi, Alireza (2021). "3D U-Net: A Voxel-based method in binding site prediction of protein structure".
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Nazem, Fatemeh; Ghasemi, Fahimeh; Fassihi, Afshin; Mehri Dehnavi, Alireza (2024). "Deep attention network for identifying ligand-protein binding sites".
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Methotrexate inhibits dihydrofolate reductase by outcompeting the substrate folic acid. Binding site in blue, inhibitor in green, and substrate in black.
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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
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In the scope of cancer, ligands that are edited to have a similar appearance to the natural ligand are used to inhibit tumor growth. For example,
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Protein inhibition by inhibitor binding may induce obstruction in pathway regulation, homeostatic regulation and physiological function.
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A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule.
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In the context of the blood, an example of competitive binding is carbon monoxide which competes with oxygen for the active site on
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Types of enzymes that can perform these actions include oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases.
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Binding curves describe the binding behavior of ligand to a protein. Curves can be characterized by their shape,
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Konc J, Janežič D (April 2014). "Binding site comparison for function prediction and pharmaceutical discovery".
272:” human proteome from ~40% to ~78% of disease-associated proteins. The binding sites have been investigated by: 2206:
Jones S, Thornton JM (September 1997). "Analysis of protein-protein interaction sites using surface patches".
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Sigmoidal versus hyperbolic binding patterns demonstrate cooperative and noncooperative character of enzymes.
17: 2106:"Proteins and Their Interacting Partners: An Introduction to Protein-Ligand Binding Site Prediction Methods" 280:
with Markov state model and with biophysical experiments, and cryptic-site index that is based on relative
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Peng J, Li XP (November 2018). "Apolipoprotein A-IV: A potential therapeutic target for atherosclerosis".
1448:"CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites" 1446:
Cimermancic P, Weinkam P, Rettenmaier TJ, Bichmann L, Keedy DA, Woldeyes RA, et al. (February 2016).
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The parts of a macromolecule that directly participate in its specific combination with another molecule.
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In cardiovascular illnesses, drugs such as beta blockers are used to treat patients with hypertension.
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Competitive and noncompetitive enzyme binding at active and regulatory (allosteric) site respectively.
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Amos-Binks A, Patulea C, Pitre S, Schoenrock A, Gui Y, Green JR, Golshani A, Dehne F (June 2011).
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ligands, in which single or multiple types of molecule affects enzyme activity respectively.
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Modeling with binding curves are useful when evaluating the binding affinities of oxygen to
2427: 1982: 1569: 1510: 872: 460: 439: 383: 371: 75: 51: 374:, shutting off production of DNA, RNA and proteins. Inhibition of this function represses 241:
Enzymes that are highly regulated are often essential in metabolic pathways. For example,
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enzyme's likelihood to bind to a second substrate. Regulatory site ligands can involve
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Montecucco C, MolgĂł J (June 2005). "Botulinal neurotoxins: revival of an old killer".
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applied to "CryptoSite" data set, Extension of "CryptoSite" data set, long timescale
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Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG (October 2002).
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Biochemical differences between different organisms and humans are useful for
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Glucose binds to hexokinase in the active site at the beginning of glycolysis.
2554: 2360: 2319: 1753: 1628: 1257: 964: 499: 43: 30: 1582: 1523: 1411: 86:. Binding to protein binding sites is most often reversible (transient and 2219: 2184: 2141: 2090: 2014: 1995: 1952: 1908: 1851: 1816: 1720: 1685: 1636: 1601: 1542: 1483: 1429: 1380: 1331: 1188: 904: 792: 743: 679: 630: 518: 390: 363: 359: 269: 111: 87: 2227: 2122: 1044: 987: 2533: 2468: 2304: 192: 1143:. United States of America: W.H. Freeman and Company. pp. 787–792. 1798: 774: 612: 401: 337: 313: 246: 1783:"Protein function annotation by local binding site surface similarity" 1712: 1676: 1659: 597:"Protein function annotation by local binding site surface similarity" 130: 54:. The binding partner of the macromolecule is often referred to as a 2507: 2481: 1445: 379: 317: 216: 1556:
Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S (March 2015).
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is decreased in the presence of an enzyme to catalyze the reaction.
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or hyperbolic, which reflect whether or not the protein exhibits
71: 47: 917: 721: 480: 78:. The binding event is often, but not always, accompanied by a 2520: 2290: 1499:"Exploring the structural origins of cryptic sites on proteins" 1077:
Principles and Techniques of Biochemistry and Molecular Biology
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Principles and Techniques of Biochemistry and Molecular Biology
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in the blood. Hemoglobin, which has four heme groups, exhibits
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Molecule-specific coordinate bonding area in biological systems
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Competitive inhibitors are also largely found commercially.
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active site. This interaction inhibits the synthesis of
253: 90:), but can also be covalent reversible or irreversible. 1959: 1780: 594: 1781:
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Enzymes incur catalysis by binding more strongly to
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Journal of Bioinformatics and Computational Biology
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Helvetian Press. 877:2018PLoSO..1398632K 322:cooperative binding 243:phosphofructokinase 153:activation energy. 100:signal transduction 2566:Structural biology 2392:Enzyme superfamily 2325:Enzyme promiscuity 1799:10.1002/prot.24450 1035:Clarke KG (2013). 775:10.1039/c6mb00231e 613:10.1002/prot.24450 487:BMC Bioinformatics 356: 298: 222: 204:muscle contraction 139: 36: 2571:Protein structure 2548: 2547: 2047:978-1-57340-135-7 1713:10.1021/la3030827 1677:10.1002/bmb.20979 1623:(45): 9977–9986. 1357:(12): 3265–3276. 1308:(19): 3871–3888. 1282:978-0-7506-0561-8 1150:978-1-4641-2609-3 1139:Morris J (2016). 1125:978-1-62870-844-8 1054:978-1-78242-167-2 1021:978-1-4051-8740-4 997:978-1-119-45501-1 708:978-1-119-23848-5 581:978-1-4200-1618-5 552:978-1-62870-176-0 376:neoplastic growth 344: 143:transition states 135:Activation energy 104:neurotransmitters 68:second messengers 64:enzyme substrates 42:is a region on a 16:(Redirected from 2578: 2561:Chemical bonding 2428:Hanes–Woolf plot 2371:Enzyme activator 2366:Enzyme inhibitor 2340:Enzyme catalysis 2284: 2277: 2270: 2261: 2260: 2232: 2231: 2203: 2197: 2196: 2159: 2146: 2145: 2135: 2125: 2116:(12): 29829–42. 2101: 2095: 2094: 2066: 2060: 2059: 2025: 2019: 2018: 2008: 1998: 1966: 1957: 1956: 1946: 1922: 1913: 1912: 1902: 1870: 1864: 1863: 1827: 1821: 1820: 1810: 1778: 1772: 1771: 1765: 1757: 1731: 1725: 1724: 1707:(41): 14665–71. 1696: 1690: 1689: 1679: 1655: 1649: 1648: 1612: 1606: 1605: 1595: 1585: 1553: 1547: 1546: 1536: 1526: 1494: 1488: 1487: 1477: 1467: 1443: 1434: 1433: 1423: 1406:(8): 1711–1727. 1391: 1385: 1384: 1374: 1342: 1336: 1335: 1325: 1293: 1287: 1286: 1268: 1262: 1261: 1235: 1226: 1225: 1199: 1193: 1192: 1164: 1155: 1154: 1136: 1130: 1129: 1111: 1105: 1104: 1102: 1101: 1068: 1059: 1058: 1032: 1026: 1025: 1008: 1002: 1001: 975: 969: 968: 942: 936: 935: 915: 909: 908: 898: 888: 856: 850: 849: 844:Ahern K (2015). 841: 835: 834: 808: 797: 796: 786: 754: 748: 747: 719: 713: 712: 690: 684: 683: 673: 641: 635: 634: 624: 592: 586: 585: 563: 557: 556: 538: 523: 522: 512: 502: 478: 472: 471: 457: 451: 450: 436: 419:hydrogen bonding 372:tetrahydrofolate 364:chemotherapeutic 342: 336:. For instance, 334:drug development 116:steroid hormones 21: 2586: 2585: 2581: 2580: 2579: 2577: 2576: 2575: 2551: 2550: 2549: 2544: 2456:Oxidoreductases 2442: 2418:Enzyme kinetics 2406: 2402:List of enzymes 2375: 2344: 2315:Catalytic triad 2293: 2288: 2241: 2236: 2235: 2204: 2200: 2160: 2149: 2102: 2098: 2067: 2063: 2048: 2026: 2022: 1981:(21): 13481–6. 1967: 1960: 1923: 1916: 1871: 1867: 1828: 1824: 1779: 1775: 1759: 1758: 1746: 1732: 1728: 1697: 1693: 1656: 1652: 1613: 1609: 1554: 1550: 1495: 1491: 1444: 1437: 1392: 1388: 1343: 1339: 1294: 1290: 1283: 1269: 1265: 1250: 1236: 1229: 1222: 1200: 1196: 1165: 1158: 1151: 1137: 1133: 1126: 1112: 1108: 1099: 1097: 1095: 1069: 1062: 1055: 1033: 1029: 1022: 1010: 1009: 1005: 998: 976: 972: 957: 943: 939: 916: 912: 871:(6): e0198632. 857: 853: 842: 838: 831: 809: 800: 769:(10): 3067–87. 755: 751: 720: 716: 709: 691: 687: 642: 638: 593: 589: 582: 564: 560: 553: 539: 526: 479: 475: 459: 458: 454: 438: 437: 433: 428: 410: 398:Botulinum toxin 345:-transpeptidase 330: 290: 265: 256: 227: 225:Allosteric site 195: 189: 184: 159: 128: 120:Electric charge 96: 28: 23: 22: 15: 12: 11: 5: 2584: 2574: 2573: 2568: 2563: 2546: 2545: 2543: 2542: 2529: 2516: 2503: 2490: 2477: 2464: 2450: 2448: 2444: 2443: 2441: 2440: 2435: 2430: 2425: 2420: 2414: 2412: 2408: 2407: 2405: 2404: 2399: 2394: 2389: 2383: 2381: 2380:Classification 2377: 2376: 2374: 2373: 2368: 2363: 2358: 2352: 2350: 2346: 2345: 2343: 2342: 2337: 2332: 2327: 2322: 2317: 2312: 2307: 2301: 2299: 2295: 2294: 2287: 2286: 2279: 2272: 2264: 2258: 2257: 2252: 2240: 2239:External links 2237: 2234: 2233: 2198: 2147: 2096: 2061: 2046: 2020: 1958: 1937:(6): 694–703. 1931:The Oncologist 1914: 1865: 1822: 1773: 1744: 1726: 1691: 1650: 1607: 1548: 1489: 1458:(4): 709–719. 1435: 1386: 1337: 1288: 1281: 1263: 1249:978-0956478115 1248: 1227: 1220: 1194: 1156: 1149: 1131: 1124: 1106: 1093: 1060: 1053: 1027: 1020: 1003: 996: 970: 955: 937: 910: 851: 836: 829: 798: 749: 714: 707: 685: 636: 587: 580: 558: 551: 524: 473: 452: 440:"Binding site" 430: 429: 427: 424: 415:hydrophobicity 409: 406: 329: 326: 289: 288:Binding curves 286: 264: 261: 255: 252: 226: 223: 191:Main article: 188: 185: 183: 180: 158: 155: 127: 124: 95: 92: 26: 9: 6: 4: 3: 2: 2583: 2572: 2569: 2567: 2564: 2562: 2559: 2558: 2556: 2540: 2536: 2535: 2530: 2527: 2523: 2522: 2517: 2514: 2510: 2509: 2504: 2501: 2497: 2496: 2491: 2488: 2484: 2483: 2478: 2475: 2471: 2470: 2465: 2462: 2458: 2457: 2452: 2451: 2449: 2445: 2439: 2436: 2434: 2431: 2429: 2426: 2424: 2421: 2419: 2416: 2415: 2413: 2409: 2403: 2400: 2398: 2397:Enzyme family 2395: 2393: 2390: 2388: 2385: 2384: 2382: 2378: 2372: 2369: 2367: 2364: 2362: 2361:Cooperativity 2359: 2357: 2354: 2353: 2351: 2347: 2341: 2338: 2336: 2333: 2331: 2328: 2326: 2323: 2321: 2320:Oxyanion hole 2318: 2316: 2313: 2311: 2308: 2306: 2303: 2302: 2300: 2296: 2292: 2285: 2280: 2278: 2273: 2271: 2266: 2265: 2262: 2256: 2253: 2250: 2246: 2245:Binding Sites 2243: 2242: 2229: 2225: 2221: 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1667: 1663: 1653: 1620: 1616: 1610: 1565: 1561: 1551: 1506: 1502: 1492: 1455: 1451: 1403: 1399: 1389: 1354: 1351:Cell Reports 1350: 1340: 1305: 1301: 1291: 1272: 1266: 1239: 1203: 1197: 1172: 1168: 1140: 1134: 1115: 1109: 1098:. Retrieved 1076: 1036: 1030: 1011: 1006: 979: 973: 946: 940: 923: 919: 913: 868: 864: 854: 845: 839: 812: 766: 762: 752: 727: 723: 717: 698: 688: 653: 649: 639: 604: 600: 590: 571: 561: 542: 490: 486: 476: 468: 464: 455: 447: 443: 434: 411: 395: 388: 360:Methotrexate 357: 331: 328:Applications 311: 299: 266: 257: 240: 236:heterotropic 228: 208: 200:cross-bridge 196: 176: 170: 163: 160: 151: 148: 140: 97: 88:non-covalent 40:binding site 39: 37: 2305:Active site 1885:: 121–128. 656:: 110–116. 306:cooperative 193:Active site 187:Active site 52:specificity 2555:Categories 2508:Isomerases 2482:Hydrolases 2349:Regulation 1100:2018-11-01 426:References 408:Prediction 402:neurotoxin 382:and adult 338:penicillin 314:hemoglobin 232:homotropic 157:Inhibition 46:such as a 2387:EC number 1838:: 87–92. 1762:cite book 1754:937824456 1645:226244554 1258:760830351 1073:"Enzymes" 965:487962823 461:"Ligands" 380:psoriasis 318:myoglobin 302:sigmoidal 270:druggable 247:catabolic 126:Catalysis 2411:Kinetics 2335:Cofactor 2298:Activity 2185:27796788 2142:26694353 2091:15907915 2056:38187984 2015:12359872 1953:16794248 1909:30339776 1860:53023273 1852:30352313 1817:24166661 1787:Proteins 1721:22978617 1701:Langmuir 1686:27228905 1637:33140952 1602:25730859 1543:29581267 1484:26854760 1430:31004156 1381:29562182 1332:31306664 1189:24878342 1175:: 34–9. 905:29874286 865:PLOS ONE 793:27452673 744:33866960 680:27599186 631:24166661 601:Proteins 519:21635751 94:Function 84:function 72:hormones 2521:Ligases 2291:Enzymes 2228:9299342 2193:6705144 2133:4691145 1983:Bibcode 1900:6289839 1808:3949165 1593:4352775 1570:Bibcode 1534:5899430 1511:Bibcode 1475:4794384 1421:6657754 1372:5873459 1323:6739599 896:5991966 873:Bibcode 784:5030169 671:5107367 622:3949165 510:3120708 493:: 225. 48:protein 2495:Lyases 2251:(MeSH) 2226:  2191:  2183:  2140:  2130:  2089:  2054:  2044:  2013:  2006:129699 2003:  1951:  1907:  1897:  1858:  1850:  1815:  1805:  1752:  1742:  1719:  1684:  1643:  1635:  1600:  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2173:doi 2128:PMC 2118:doi 2079:doi 2034:doi 2001:PMC 1991:doi 1939:doi 1895:PMC 1887:doi 1883:660 1840:doi 1836:139 1803:PMC 1795:doi 1709:doi 1672:doi 1625:doi 1621:124 1588:PMC 1578:doi 1566:112 1529:PMC 1519:doi 1507:115 1470:PMC 1460:doi 1456:428 1416:PMC 1408:doi 1367:PMC 1359:doi 1318:PMC 1310:doi 1306:431 1208:doi 1177:doi 1081:doi 1041:doi 984:doi 928:doi 891:PMC 881:doi 817:doi 779:PMC 771:doi 732:doi 666:PMC 658:doi 617:PMC 609:doi 505:PMC 495:doi 62:), 2557:: 2222:. 2210:. 2187:. 2179:. 2169:75 2167:. 2150:^ 2136:. 2126:. 2114:16 2112:. 2108:. 2085:. 2073:. 2050:. 2040:. 2032:. 2009:. 1999:. 1989:. 1979:99 1977:. 1973:. 1961:^ 1947:. 1935:11 1933:. 1929:. 1917:^ 1903:. 1893:. 1881:. 1877:. 1854:. 1846:. 1834:. 1811:. 1801:. 1791:82 1789:. 1785:. 1764:}} 1760:{{ 1748:. 1715:. 1705:28 1703:. 1680:. 1668:45 1666:. 1662:. 1639:. 1631:. 1619:. 1596:. 1586:. 1576:. 1564:. 1560:. 1537:. 1527:. 1517:. 1505:. 1501:. 1478:. 1468:. 1454:. 1450:. 1438:^ 1424:. 1414:. 1404:36 1402:. 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883:: 875:: 833:. 819:: 795:. 773:: 746:. 734:: 711:. 682:. 660:: 633:. 611:: 584:. 555:. 521:. 497:: 268:“ 20:)

Index

Binding sites

macromolecule
protein
specificity
ligand
protein–protein interaction
enzyme substrates
second messengers
hormones
allosteric modulators
conformational change
function
non-covalent
signal transduction
neurotransmitters
toxins
neuropeptides
steroid hormones
Electric charge

Activation energy
transition states
Competitive inhibitors
Uncompetitive inhibitors
Active site
cross-bridge
muscle contraction
heme

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