Exploring the structural origins of cryptic sites on proteins

Proceedings of the National Academy of Sciences of the United States of America

Volumn 115, Issue 15, 2018, Pages E3416-E3425

  Beglov, Dmitri ^a   Hall, David R ^b   Wakefield, Amanda E ^a,c   Luo, Lingqi ^d   Allen, Karen N ^c   Kozakov, Dima ^a,e,f   Whitty, Adrian ^c   Vajda, Sandor ^a,c  

^a Boston University   (United States)

^b Acpharis Inc   (United States)

^c Boston University   (United States)

^d BOSTON UNIVERSITY   (United States)

^e Stony Brook University   (United States)

^f STONY BROOK UNIVERSITY   (United States)

Author keywords

Binding hot spot; Drug discovery; Druggability; Protein flexibility; Protein ligand interaction

Indexed keywords

PROTEIN; LIGAND; PROTEIN BINDING;

ARTICLE; BINDING SITE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; HUMAN; LIGAND BINDING; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN INTERACTION; PROTEIN STRUCTURE; X RAY; CHEMISTRY; MOLECULAR DYNAMICS;

BINDING SITES; LIGANDS; MOLECULAR DYNAMICS SIMULATION; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEINS;

EID: 85045078399     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1711490115     Document Type: Article

References (51)

1. Laskowski RA, Luscombe NM, Swindells MB, Thornton JM (1996) Protein clefts in molecular recognition and function. Protein Sci 5:2438-2452.
2. Durrant JD, McCammon JA (2011) Molecular dynamics simulations and drug discovery. BMC Biol 9:71.
3. Bowman GR, Geissler PL (2012) Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites. Proc Natl Acad Sci USA 109: 11681-11686.
4. Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S (2015) Discovery of multiple hidden allosteric sites by combining Markov state models and experiments. Proc Natl Acad Sci USA 112:2734-2739.
5. Cimermancic P, et al. (2016) CryptoSite: Expanding the druggable proteome by characterization and prediction of cryptic binding sites. J Mol Biol 428:709-719.
6. Oleinikovas V, Saladino G, Cossins BP, Gervasio FL (2016) Understanding cryptic pocket formation in protein targets by enhanced sampling simulations. J Am Chem Soc 138:14257-14263.
7. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1: 727-730.
8. Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2: 112-118.
9. Hardy JA, Wells JA (2004) Searching for new allosteric sites in enzymes. Curr Opin Struct Biol 14:706-715.
10. Arkin MR, Whitty A (2009) The road less traveled: Modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr Opin Chem Biol 13: 284-290.
11. Ludlow RF, Verdonk ML, Saini HK, Tickle IJ, Jhoti H (2015) Detection of secondary binding sites in proteins using fragment screening. Proc Natl Acad Sci USA 112: 15910-15915.
12. Erlanson DA, Wells JA, Braisted AC (2004) Tethering: Fragment-based drug discovery. Annu Rev Biophys Biomol Struct 33:199-223.
13. Lawson AD (2012) Antibody-enabled small-molecule drug discovery. Nat Rev Drug Discov 11:519-525.
14. Eyrisch S, Helms V (2007) Transient pockets on protein surfaces involved in protein-protein interaction. J Med Chem 50:3457-3464.
15. Ulucan O, Eyrisch S, Helms V (2012) Druggability of dynamic protein-protein interfaces. Curr Pharm Des 18:4599-4606.
16. Johnson DK, Karanicolas J (2013) Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface. PLoS Comput Biol 9:e1002951.
17. DeLano WL (2002) Unraveling hot spots in binding interfaces: Progress and challenges. Curr Opin Struct Biol 12:14-20.
18. Ciulli A, Williams G, Smith AG, Blundell TL, Abell C (2006) Probing hot spots at protein-ligand binding sites: A fragment-based approach using biophysical methods. J Med Chem 49:4992-5000.
19. Metz A, et al. (2012) Hot spots and transient pockets: Predicting the determinants of small-molecule binding to a protein-protein interface. J Chem Inf Model 52:120-133.
20. Hall DR, Kozakov D, Whitty A, Vajda S (2015) Lessons from hot spot analysis for fragment-based drug discovery. Trends Pharmacol Sci 36:724-736.
21. Kozakov D, et al. (2015) New frontiers in druggability. J Med Chem 58:9063-9088.
22. Kozakov D, et al. (2015) The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins. Nat Protoc 10:733-755.
23. Mattos C, Ringe D (1996) Locating and characterizing binding sites on proteins. Nat Biotechnol 14:595-599.
24. Hajduk PJ, Huth JR, Fesik SW (2005) Druggability indices for protein targets derived from NMR-based screening data. J Med Chem 48:2518-2525.
25. Brenke R, et al. (2009) Fragment-based identification of druggable 'hot spots' of proteins using Fourier domain correlation techniques. Bioinformatics 25:621-627.
26. Grove LE, Hall DR, Beglov D, Vajda S, Kozakov D (2013) FTFlex: Accounting for binding site flexibility to improve fragment-based identification of druggable hot spots. Bioinformatics 29:1218-1219.
27. Landon MR, et al. (2009) Detection of ligand binding hot spots on protein surfaces via fragment-based methods: Application to DJ-1 and glucocerebrosidase. J Comput Aided Mol Des 23:491-500.
28. Kozakov D, Chuang GY, Beglov D, Vajda S (2010) Where does amantadine bind to the influenza virus M2 proton channel? Trends Biochem Sci 35:471-475.
29. Kozakov D, et al. (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci USA 108:13528-13533.
30. Hall DH, et al. (2011) Robust identification of binding hot spots using continuum electrostatics: Application to hen egg-white lysozyme. J Am Chem Soc 133:20668-20671.
31. Buhrman G, et al. (2011) Analysis of binding site hot spots on the surface of Ras GTPase. J Mol Biol 413:773-789.
32. Golden MS, et al. (2013) Comprehensive experimental and computational analysis of binding energy hot spots at the NF-κB essential modulator/IKKβ protein-protein interface. J Am Chem Soc 135:6242-6256.
33. Landon MR, et al. (2008) Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble. Chem Biol Drug Des 71:106-116.
34. Wassman CD, et al. (2013) Computational identification of a transiently open L1/ S3 pocket for reactivation of mutant p53. Nat Commun 4:1407.
35. Ngan CH, et al. (2012) FTSite: High accuracy detection of ligand binding sites on unbound protein structures. Bioinformatics 28:286-287.
36. Alexandrov N, Shindyalov I (2003) PDP: Protein domain parser. Bioinformatics 19: 429-430.
37. Arkin MR, et al. (2003) Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci USA 100:1603-1608.
38. Hyde J, Braisted AC, Randal M, Arkin MR (2003) Discovery and characterization of cooperative ligand binding in the adaptive region of interleukin-2. Biochemistry 42: 6475-6483.
39. Horn JR, Shoichet BK (2004) Allosteric inhibition through core disruption. J Mol Biol 336:1283-1291.
40. Berman HM, et al. (2000) The protein data bank. Nucleic Acids Res 28:235-242.
41. Wilson KP, et al. (1996) Crystal structure of p38 mitogen-activated protein kinase. J Biol Chem 271:27696-27700.
42. Wang Y, Kaiser CE, Frett B, Li HY (2013) Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. J Med Chem 56: 5219-5230.
43. Sun Q, et al. (2012) Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew Chem Int Ed Engl 51:6140-6143.
44. Maurer T, et al. (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 109: 5299-5304.
45. Barr AJ (2010) Protein tyrosine phosphatases as drug targets: Strategies and challenges of inhibitor development. Future Med Chem 2:1563-1576.
46. Wiesmann C, et al. (2004) Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 11:730-737.
47. Li S, et al. (2014) The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B. PLoS One 9:e97668.
48. Daniels KG, Suo Y, Oas TG (2015) Conformational kinetics reveals affinities of protein conformational states. Proc Natl Acad Sci USA 112:9352-9357.
49. Greives N, Zhou HX (2014) Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit. Proc Natl Acad Sci USA 111:10197-10202.
50. Zhou HX (2010) From induced fit to conformational selection: A continuum of binding mechanism controlled by the timescale of conformational transitions. Biophys J 98:L15-L17.
51. Thompson JD, Gibson TJ, Higgins DG (2002) Multiple sequence alignment using ClustalW and ClustalX. Curr Protoc Bioinformatics Chap 2:Unit 2.3.