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Hot-spot mimicry of a cytokine receptor by a small molecule.

Thanos CD, DeLano WL, Wells JA
Proc Natl Acad Sci U S A 103 15422-7 (2006)
Cited: 84 times
EuropePMC logo PMID: 17032757

Abstract

Protein-protein complexes remain enticing, but extremely challenging, targets for small-molecule drug discovery. In a rare example described earlier, a high-affinity small molecule, SP4206 (Kd approximately 70 nM), was found to block binding of the IL-2alpha receptor (IL-2Ralpha) to IL-2 (Kd approximately 10 nM). Recently, the structure of the IL-2/IL-2Ralpha complex was solved [Rickert, M., Wang, X., Boulanger, M. J., Goriatcheva, N., Garcia, K. C. (2005) Science 308:1477-1480]. Using structural and functional analysis, we compare how SP4206 mimics the 83-fold larger IL-2Ralpha in binding IL-2. The binding free energy per contact atom (ligand efficiency) for SP4206 is about twice that of the receptor because of a smaller, but overlapping, contact epitope that insinuates into grooves and cavities not accessed by the receptor. Despite its independent design, the small molecule has a similar, but more localized, charge distribution compared with IL-2Ralpha. Mutational studies show that SP4206 targets virtually the same critical "hot-spot" residues on IL-2 that drive binding of IL-2Ralpha. Moreover, a mutation that enhances binding to the IL-2Ralpha near these hot spots also enhances binding to SP4206. Although the protein and small molecule do bind the same hot spot, they trap very different conformations of IL-2 because of its flexible nature. Our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots.

Articles - 1qvn mentioned but not cited (4)

  1. Hot-spot mimicry of a cytokine receptor by a small molecule. Thanos CD, DeLano WL, Wells JA. Proc Natl Acad Sci U S A 103 15422-15427 (2006)
  2. HADDOCK(2P2I): a biophysical model for predicting the binding affinity of protein-protein interaction inhibitors. Kastritis PL, Rodrigues JP, Bonvin AM. J Chem Inf Model 54 826-836 (2014)
  3. Fractal Dimensions of Macromolecular Structures. Todoroff N, Kunze J, Schreuder H, Hessler G, Baringhaus KH, Schneider G. Mol Inform 33 588-596 (2014)
  4. Exploration of the mechanism by which Huangqi Guizhi Wuwu decoction inhibits Lps-induced inflammation by regulating macrophage polarization based on network pharmacology. Wang S, Ji T, Wang L, Qu Y, Wang X, Wang W, Lv M, Wang Y, Li X, Jiang P. BMC Complement Med Ther 23 8 (2023)


Reviews citing this publication (26)

  1. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Wells JA, McClendon CL. Nature 450 1001-1009 (2007)
  2. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Scott DE, Bayly AR, Abell C, Skidmore J. Nat Rev Drug Discov 15 533-550 (2016)
  3. Structural biology of shared cytokine receptors. Wang X, Lupardus P, Laporte SL, Garcia KC. Annu Rev Immunol 27 29-60 (2009)
  4. Oncogenic protein interfaces: small molecules, big challenges. Nero TL, Morton CJ, Holien JK, Wielens J, Parker MW. Nat Rev Cancer 14 248-262 (2014)
  5. Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell. Wei G, Xi W, Nussinov R, Ma B. Chem Rev 116 6516-6551 (2016)
  6. Structural biology and drug discovery of difficult targets: the limits of ligandability. Surade S, Blundell TL. Chem Biol 19 42-50 (2012)
  7. Peptide therapeutics: targeting the undruggable space. Tsomaia N. Eur J Med Chem 94 459-470 (2015)
  8. Insights into cytokine-receptor interactions from cytokine engineering. Spangler JB, Moraga I, Mendoza JL, Garcia KC. Annu Rev Immunol 33 139-167 (2015)
  9. The design, structures and therapeutic potential of protein epitope mimetics. Robinson JA, Demarco S, Gombert F, Moehle K, Obrecht D. Drug Discov Today 13 944-951 (2008)
  10. Biophysical and computational fragment-based approaches to targeting protein-protein interactions: applications in structure-guided drug discovery. Winter A, Higueruelo AP, Marsh M, Sigurdardottir A, Pitt WR, Blundell TL. Q Rev Biophys 45 383-426 (2012)
  11. Computational prediction of protein hot spot residues. Morrow JK, Zhang S. Curr Pharm Des 18 1255-1265 (2012)
  12. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Zhao H, Alam A, San CY, Eguchi S, Chen Q, Lian Q, Ma D. Brain Res 1665 1-21 (2017)
  13. Drug discovery and the human kinome: recent trends. Eglen R, Reisine T. Pharmacol Ther 130 144-156 (2011)
  14. Established and emerging trends in computational drug discovery in the structural genomics era. Taboureau O, Baell JB, Fernández-Recio J, Villoutreix BO. Chem Biol 19 29-41 (2012)
  15. Neutralizing endogenous chemokines with small molecules. Principles and potential therapeutic applications. Galzi JL, Hachet-Haas M, Bonnet D, Daubeuf F, Lecat S, Hibert M, Haiech J, Frossard N. Pharmacol Ther 126 39-55 (2010)
  16. Cytokine-receptor interactions as drug targets. Schreiber G, Walter MR. Curr Opin Chem Biol 14 511-519 (2010)
  17. The FRS2 family of docking/scaffolding adaptor proteins as therapeutic targets of cancer treatment. Sato T, Gotoh N. Expert Opin Ther Targets 13 689-700 (2009)
  18. In search of small molecules blocking interactions between HIV proteins and intracellular cofactors. Busschots K, De Rijck J, Christ F, Debyser Z. Mol Biosyst 5 21-31 (2009)
  19. BAFF-targeting therapy, a promising strategy for treating autoimmune diseases. Sun J, Lin Z, Feng J, Li Y, Shen B. Eur J Pharmacol 597 1-5 (2008)
  20. Druggable orthosteric and allosteric hot spots to target protein-protein interactions. Ma B, Nussinov R. Curr Pharm Des 20 1293-1301 (2014)
  21. Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action. Rusnati M, Urbinati C, Bonifacio S, Presta M, Taraboletti G. Pharmaceuticals (Basel) 3 1241-1278 (2010)
  22. Oncogenic Signaling Adaptor Proteins. Luo LY, Hahn WC. J Genet Genomics 42 521-529 (2015)
  23. Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents. Chou CC, Salunke SB, Kulp SK, Chen CS. J Cell Biochem 115 611-624 (2014)
  24. In silico Approaches for the Design and Optimization of Interfering Peptides Against Protein-Protein Interactions. Hashemi ZS, Zarei M, Fath MK, Ganji M, Farahani MS, Afsharnouri F, Pourzardosht N, Khalesi B, Jahangiri A, Rahbar MR, Khalili S. Front Mol Biosci 8 669431 (2021)
  25. Cell-free Biosynthesis of Peptidomimetics. Lee K, Willi JA, Cho N, Kim I, Jewett MC, Lee J. Biotechnol Bioprocess Eng 1-17 (2023)
  26. In silico identification of an interferon inhibitor. Kaiser M, Ottmann C. ChemMedChem 7 555-557 (2012)

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  1. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P, Pande VS, Fathman CG, Boyman O, Garcia KC. Nature 484 529-533 (2012)
  2. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, Nehama D, Rajadas J, Longo FM. J Clin Invest 120 1774-1785 (2010)
  3. The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins. Kozakov D, Grove LE, Hall DR, Bohnuud T, Mottarella SE, Luo L, Xia B, Beglov D, Vajda S. Nat Protoc 10 733-755 (2015)
  4. Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles. McClendon CL, Friedland G, Mobley DL, Amirkhani H, Jacobson MP. J Chem Theory Comput 5 2486-2502 (2009)
  5. HotPoint: hot spot prediction server for protein interfaces. Tuncbag N, Keskin O, Gursoy A. Nucleic Acids Res 38 W402-6 (2010)
  6. Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms. Spangler JB, Tomala J, Luca VC, Jude KM, Dong S, Ring AM, Votavova P, Pepper M, Kovar M, Garcia KC. Immunity 42 815-825 (2015)
  7. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. Lupardus PJ, Garcia KC. J Mol Biol 382 931-941 (2008)
  8. KFC Server: interactive forecasting of protein interaction hot spots. Darnell SJ, LeGault L, Mitchell JC. Nucleic Acids Res 36 W265-9 (2008)
  9. Designing focused chemical libraries enriched in protein-protein interaction inhibitors using machine-learning methods. Reynès C, Host H, Camproux AC, Laconde G, Leroux F, Mazars A, Deprez B, Fahraeus R, Villoutreix BO, Sperandio O. PLoS Comput Biol 6 e1000695 (2010)
  10. A novel class of small molecule inhibitors of Hsp90. Yi F, Regan L. ACS Chem Biol 3 645-654 (2008)
  11. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade. Zhang F, Wei H, Wang X, Bai Y, Wang P, Wu J, Jiang X, Wang Y, Cai H, Xu T, Zhou A. Cell Discov 3 17004 (2017)
  12. A simple model of backbone flexibility improves modeling of side-chain conformational variability. Friedland GD, Linares AJ, Smith CA, Kortemme T. J Mol Biol 380 757-774 (2008)
  13. A single-domain llama antibody potently inhibits the enzymatic activity of botulinum neurotoxin by binding to the non-catalytic alpha-exosite binding region. Dong J, Thompson AA, Fan Y, Lou J, Conrad F, Ho M, Pires-Alves M, Wilson BA, Stevens RC, Marks JD. J Mol Biol 397 1106-1118 (2010)
  14. Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds. Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis DS, Stravalaci M, Tomaselli S, Giavazzi R, Rusnati M, Presta M, Zetta L, Mosher DF, Ribatti D, Gobbi M, Taraboletti G. J Biol Chem 285 8733-8742 (2010)
  15. Comparing Conformational Ensembles Using the Kullback-Leibler Divergence Expansion. McClendon CL, Hua L, Barreiro A, Jacobson MP. J Chem Theory Comput 8 2115-2126 (2012)
  16. Exploring the capacity of minimalist protein interfaces: interface energetics and affinity maturation to picomolar KD of a single-domain antibody with a flat paratope. Koide A, Tereshko V, Uysal S, Margalef K, Kossiakoff AA, Koide S. J Mol Biol 373 941-953 (2007)
  17. The overlap of small molecule and protein binding sites within families of protein structures. Davis FP, Sali A. PLoS Comput Biol 6 e1000668 (2010)
  18. Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein. Oh M, Lee JH, Wang W, Lee HS, Lee WS, Burlak C, Im W, Hoang QQ, Lim HS. Proc Natl Acad Sci U S A 111 11007-11012 (2014)
  19. Alignment of non-covalent interactions at protein-protein interfaces. Zhu H, Sommer I, Lengauer T, Domingues FS. PLoS One 3 e1926 (2008)
  20. Deregulations in the cyclin-dependent kinase-9-related pathway in cancer: implications for drug discovery and development. Romano G. ISRN Oncol 2013 305371 (2013)
  21. Two structurally different rituximab-specific CD20 mimotope peptides reveal that rituximab recognizes two different CD20-associated epitopes. Perosa F, Favoino E, Vicenti C, Guarnera A, Racanelli V, De Pinto V, Dammacco F. J Immunol 182 416-423 (2009)
  22. Differences between high- and low-affinity complexes of enzymes and nonenzymes. Carlson HA, Smith RD, Khazanov NA, Kirchhoff PD, Dunbar JB, Benson ML. J Med Chem 51 6432-6441 (2008)
  23. Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab. Zhang F, Qi X, Wang X, Wei D, Wu J, Feng L, Cai H, Wang Y, Zeng N, Xu T, Zhou A, Zheng Y. Oncotarget 8 90215-90224 (2017)
  24. Structural insight into the kinetics and DeltaCp of interactions between TEM-1 beta-lactamase and beta-lactamase inhibitory protein (BLIP). Wang J, Palzkill T, Chow DC. J Biol Chem 284 595-609 (2009)
  25. Contributions of interfacial residues of human Interleukin15 to the specificity and affinity for its private alpha-receptor. Sakamoto S, Caaveiro JM, Sano E, Tanaka Y, Kudou M, Tsumoto K. J Mol Biol 389 880-894 (2009)
  26. A peptoid antagonist of VEGF receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site. Udugamasooriya DG, Ritchie C, Brekken RA, Kodadek T. Bioorg Med Chem 16 6338-6343 (2008)
  27. PRICE (PRotein Interface Conservation and Energetics): a server for the analysis of protein-protein interfaces. Guharoy M, Pal A, Dasgupta M, Chakrabarti P. J Struct Funct Genomics 12 33-41 (2011)
  28. Screening Outside the Catalytic Site: Inhibition of Macromolecular Inter-actions Through Structure-Based Virtual Ligand Screening Experiments. Sperandio O, Miteva MA, Segers K, Nicolaes GA, Villoutreix BO. Open Biochem J 2 29-37 (2008)
  29. Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy. Spangler JB, Trotta E, Tomala J, Peck A, Young TA, Savvides CS, Silveria S, Votavova P, Salafsky J, Pande VS, Kovar M, Bluestone JA, Garcia KC. J Immunol 201 2094-2106 (2018)
  30. Novel peptide ligands of RGS4 from a focused one-bead, one-compound library. Roof RA, Sobczyk-Kojiro K, Turbiak AJ, Roman DL, Pogozheva ID, Blazer LL, Neubig RR, Mosberg HI. Chem Biol Drug Des 72 111-119 (2008)
  31. Resolving hot spots in the C-terminal dimerization domain that determine the stability of the molecular chaperone Hsp90. Ciglia E, Vergin J, Reimann S, Smits SH, Schmitt L, Groth G, Gohlke H. PLoS One 9 e96031 (2014)
  32. Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan. Lawson KV, Rose TE, Harran PG. Tetrahedron 69 7683-7691 (2013)
  33. A computational tool to predict the evolutionarily conserved protein-protein interaction hot-spot residues from the structure of the unbound protein. Agrawal NJ, Helk B, Trout BL. FEBS Lett 588 326-333 (2014)
  34. Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein-Protein Interaction. Liu D, Xu D, Liu M, Knabe WE, Yuan C, Zhou D, Huang M, Meroueh SO. Biochemistry 56 1768-1784 (2017)
  35. FcαRI binding at the IgA1 CH2-CH3 interface induces long-range conformational changes that are transmitted to the hinge region. Posgai MT, Tonddast-Navaei S, Jayasinghe M, Ibrahim GM, Stan G, Herr AB. Proc Natl Acad Sci U S A 115 E8882-E8891 (2018)
  36. Proteome-wide prediction of overlapping small molecule and protein binding sites using structure. Davis FP. Mol Biosyst 7 545-557 (2011)
  37. Conformational analysis of alternative protein structures. Domingues FS, Rahnenführer J, Lengauer T. Bioinformatics 23 3131-3138 (2007)
  38. Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists. Reiter LA, Jones CS, Brissette WH, McCurdy SP, Abramov YA, Bordner J, DiCapua FM, Munchhof MJ, Rescek DM, Samardjiev IJ, Withka JM. Bioorg Med Chem Lett 18 3000-3006 (2008)
  39. The first small-molecule inhibitor of 14-3-3s: modulating the master regulator. Kaiser M, Ottmann C. Chembiochem 11 2085-2087 (2010)
  40. Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch. De Paula VS, Jude KM, Nerli S, Glassman CR, Garcia KC, Sgourakis NG. Proc Natl Acad Sci U S A 117 7183-7192 (2020)
  41. Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces. Accordino SR, Morini MA, Sierra MB, Fris JA, Appignanesi GA, Fernández A. Proteins 80 1755-1765 (2012)
  42. Arginine mimetics using α-guanidino acids: introduction of functional groups and stereochemistry adjacent to recognition guanidiniums in peptides. Balakrishnan S, Scheuermann MJ, Zondlo NJ. Chembiochem 13 259-270 (2012)
  43. Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6. Bobby R, Robustelli P, Kralicek AV, Mobli M, King GF, Grötzinger J, Dingley AJ. FEBS J 281 2471-2483 (2014)
  44. Docking and scoring: applications to drug discovery in the interactomics era. Grosdidier S, Fernández-Recio J. Expert Opin Drug Discov 4 673-686 (2009)
  45. A compound-based computational approach for the accurate determination of hot spots. Wang L, Hou Y, Quan H, Xu W, Bao Y, Li Y, Fu Y, Zou S. Protein Sci 22 1060-1070 (2013)
  46. Interaction Energetics and Druggability of the Protein-Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2). Zhong M, Lynch A, Muellers SN, Jehle S, Luo L, Hall DR, Iwase R, Carolan JP, Egbert M, Wakefield A, Streu K, Harvey CM, Ortet PC, Kozakov D, Vajda S, Allen KN, Whitty A. Biochemistry 59 563-581 (2020)
  47. Modulating Antibody Structure and Function through Directed Mutations and Chemical Rescue. Kaiser CE, Rincon Pabon JP, Khowsathit J, Castaldi MP, Kazmirski SL, Weis DD, Zhang AX, Karanicolas J. ACS Synth Biol 7 1152-1162 (2018)
  48. Getting to know each other: PPIMem, a novel approach for predicting transmembrane protein-protein complexes. Khazen G, Gyulkhandanian A, Issa T, Maroun RC. Comput Struct Biotechnol J 19 5184-5197 (2021)
  49. Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides. Price-Troska T, Yang ZZ, Diller D, Bayden A, Jarosinski M, Audie J, Ansell SM. Invest New Drugs 37 9-16 (2019)
  50. Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket. Wallon L, Khan I, Teng KW, Koide A, Zuberi M, Li J, Ketavarapu G, Traaseth NJ, O'Bryan JP, Koide S. Proc Natl Acad Sci U S A 119 e2204481119 (2022)
  51. How does a small molecule bind at a cryptic binding site? Shan Y, Mysore VP, Leffler AE, Kim ET, Sagawa S, Shaw DE. PLoS Comput Biol 18 e1009817 (2022)
  52. Identification of aggregation inhibitors of the human antibody light chain repertoire by phage display. Swift J, Saing S, Rouet R, Dudgeon K, Schofield P, Sewell W, Christ D. Protein Eng Des Sel 27 405-409 (2014)
  53. In Silico Exploration of the Trypanothione Reductase (TryR) of L. mexicana. Barrera-Téllez FJ, Prieto-Martínez FD, Hernández-Campos A, Martínez-Mayorga K, Castillo-Bocanegra R. Int J Mol Sci 24 16046 (2023)
  54. Mutational screens highlight glycosylation as a modulator of colony-stimulating factor 3 receptor (CSF3R) activity. Hollander MJ, Malaker SA, Riley NM, Perez I, Abney NM, Gray MA, Maxson JE, Cochran JR, Bertozzi CR. J Biol Chem 299 104755 (2023)


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