4bhp › Citations

Allosteric inhibition through suppression of transient conformational states.

Tzeng SR, Kalodimos CG
Nat Chem Biol 9 462-5 (2013)
Cited: 67 times
EuropePMC logo PMID: 23644478

Abstract

The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors.

Reviews citing this publication (17)

  1. Chemical exchange in biomacromolecules: past, present, and future. Palmer AG. J Magn Reson 241 3-17 (2014)
  2. Protein dynamics and function from solution state NMR spectroscopy. Kovermann M, Rogne P, Wolf-Watz M. Q Rev Biophys 49 e6 (2016)
  3. Harnessing allostery: a novel approach to drug discovery. Lu S, Li S, Zhang J. Med Res Rev 34 1242-1285 (2014)
  4. Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers. Nussinov R, Jang H, Tsai CJ, Cheng F. PLoS Comput Biol 15 e1006658 (2019)
  5. NMR Methods to Study Dynamic Allostery. Grutsch S, Brüschweiler S, Tollinger M. PLoS Comput Biol 12 e1004620 (2016)
  6. Structures of Large Protein Complexes Determined by Nuclear Magnetic Resonance Spectroscopy. Huang C, Kalodimos CG. Annu Rev Biophys 46 317-336 (2017)
  7. Molecular origins of binding affinity: seeking the Archimedean point. Kastritis PL, Bonvin AM. Curr Opin Struct Biol 23 868-877 (2013)
  8. Relaxation dispersion NMR spectroscopy for the study of protein allostery. Farber PJ, Mittermaier A. Biophys Rev 7 191-200 (2015)
  9. Allosteric control of metal-responsive transcriptional regulators in bacteria. Baksh KA, Zamble DB. J Biol Chem 295 1673-1684 (2020)
  10. Recent advances in measuring the kinetics of biomolecules by NMR relaxation dispersion spectroscopy. Ban D, Smith CA, de Groot BL, Griesinger C, Lee D. Arch Biochem Biophys 628 81-91 (2017)
  11. Asymmetric perturbations of signalling oligomers. Maksay G, Tőke O. Prog Biophys Mol Biol 114 153-169 (2014)
  12. Recent excitements in protein NMR: Large proteins and biologically relevant dynamics. Chiliveri SC, Deshmukh MV. J Biosci 41 787-803 (2016)
  13. Bacterial Transcriptional Regulators: A Road Map for Functional, Structural, and Biophysical Characterization. Pis Diez CM, Juncos MJ, Villarruel Dujovne M, Capdevila DA. Int J Mol Sci 23 2179 (2022)
  14. The "violin model": Looking at community networks for dynamic allostery. Madan LK, Welsh CL, Kornev AP, Taylor SS. J Chem Phys 158 081001 (2023)
  15. Carbon Monoxide-Sensing Transcription Factors: Regulators of Microbial Carbon Monoxide Oxidation Pathway Gene Expression. Dent MR, Weaver BR, Roberts MG, Burstyn JN. J Bacteriol 205 e0033222 (2023)
  16. cAMP Activation of the cAMP Receptor Protein, a Model Bacterial Transcription Factor. Youn H, Carranza M. J Microbiol 61 277-287 (2023)
  17. Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application. Raza SHA, Zhong R, Yu X, Zhao G, Wei X, Lei H. Mol Biotechnol (2023)

Articles citing this publication (50)

  1. NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers. Sekhar A, Kay LE. Proc Natl Acad Sci U S A 110 12867-12874 (2013)
  2. Conformational states dynamically populated by a kinase determine its function. Xie T, Saleh T, Rossi P, Kalodimos CG. Science 370 eabc2754 (2020)
  3. An excited state underlies gene regulation of a transcriptional riboswitch. Zhao B, Guffy SL, Williams B, Zhang Q. Nat Chem Biol 13 968-974 (2017)
  4. A dynamic hydrophobic core orchestrates allostery in protein kinases. Kim J, Ahuja LG, Chao FA, Xia Y, McClendon CL, Kornev AP, Taylor SS, Veglia G. Sci Adv 3 e1600663 (2017)
  5. Protein conformational dynamics dictate the binding affinity for a ligand. Seo MH, Park J, Kim E, Hohng S, Kim HS. Nat Commun 5 3724 (2014)
  6. Entropy redistribution controls allostery in a metalloregulatory protein. Capdevila DA, Braymer JJ, Edmonds KA, Wu H, Giedroc DP. Proc Natl Acad Sci U S A 114 4424-4429 (2017)
  7. Synchronous opening and closing motions are essential for cAMP-dependent protein kinase A signaling. Srivastava AK, McDonald LR, Cembran A, Kim J, Masterson LR, McClendon CL, Taylor SS, Veglia G. Structure 22 1735-1743 (2014)
  8. A designed conformational shift to control protein binding specificity. Michielssens S, Peters JH, Ban D, Pratihar S, Seeliger D, Sharma M, Giller K, Sabo TM, Becker S, Lee D, Griesinger C, de Groot BL. Angew Chem Int Ed Engl 53 10367-10371 (2014)
  9. Design of protein switches based on an ensemble model of allostery. Choi JH, Laurent AH, Hilser VJ, Ostermeier M. Nat Commun 6 6968 (2015)
  10. Conformational recognition of an intrinsically disordered protein. Krieger JM, Fusco G, Lewitzky M, Simister PC, Marchant J, Camilloni C, Feller SM, De Simone A. Biophys J 106 1771-1779 (2014)
  11. Steric mechanism of auto-inhibitory regulation of specific and non-specific DNA binding by the ETS transcriptional repressor ETV6. De S, Chan AC, Coyne HJ, Bhachech N, Hermsdorf U, Okon M, Murphy ME, Graves BJ, McIntosh LP. J Mol Biol 426 1390-1406 (2014)
  12. NMR mapping of protein conformational landscapes using coordinated behavior of chemical shifts upon ligand binding. Cembran A, Kim J, Gao J, Veglia G. Phys Chem Chem Phys 16 6508-6518 (2014)
  13. Investigating Dynamic Interdomain Allostery in Pin1. Peng JW. Biophys Rev 7 239-249 (2015)
  14. Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation. Kim J, Masterson LR, Cembran A, Verardi R, Shi L, Gao J, Taylor SS, Veglia G. Proc Natl Acad Sci U S A 112 3716-3721 (2015)
  15. Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2. Chio CM, Lim CS, Bishop AC. Biochemistry 54 497-504 (2015)
  16. Metal-dependent allosteric activation and inhibition on the same molecular scaffold: the copper sensor CopY from Streptococcus pneumoniae. Glauninger H, Zhang Y, Higgins KA, Jacobs AD, Martin JE, Fu Y, Coyne Rd HJ, Bruce KE, Maroney MJ, Clemmer DE, Capdevila DA, Giedroc DP. Chem Sci 9 105-118 (2018)
  17. Uncovering pH-dependent transient states of proteins with buried ionizable residues. Goh GB, Laricheva EN, Brooks CL. J Am Chem Soc 136 8496-8499 (2014)
  18. Evaluating the uncertainty in exchange parameters determined from off-resonance R1ρ relaxation dispersion for systems in fast exchange. Bothe JR, Stein ZW, Al-Hashimi HM. J Magn Reson 244 18-29 (2014)
  19. Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy. Sekhar A, Rumfeldt JAO, Broom HR, Doyle CM, Sobering RE, Meiering EM, Kay LE. Proc Natl Acad Sci U S A 113 E6939-E6945 (2016)
  20. Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection. Santiago C, Mudgal G, Reguera J, Recacha R, Albrecht S, Enjuanes L, Casasnovas JM. Sci Rep 7 46045 (2017)
  21. Delicate balance between functionally required flexibility and aggregation risk in a β-rich protein. Ferrolino MC, Zhuravleva A, Budyak IL, Krishnan B, Gierasch LM. Biochemistry 52 8843-8854 (2013)
  22. Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator. Capdevila DA, Huerta F, Edmonds KA, Le MT, Wu H, Giedroc DP. Elife 7 e37268 (2018)
  23. Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study. Vallurupalli P, Chakrabarti N, Pomès R, Kay LE. Chem Sci 7 3602-3613 (2016)
  24. Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q. Chen J, Yang J, Sun X, Wang Z, Cheng X, Lu W, Cai X, Hu C, Shen X, Cao P. Sci Rep 7 16458 (2017)
  25. Functional Role of Solvent Entropy and Conformational Entropy of Metal Binding in a Dynamically Driven Allosteric System. Capdevila DA, Edmonds KA, Campanello GC, Wu H, Gonzalez-Gutierrez G, Giedroc DP. J Am Chem Soc 140 9108-9119 (2018)
  26. Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex. Wurm JP, Sung S, Kneuttinger AC, Hupfeld E, Sterner R, Wilmanns M, Sprangers R. Nat Commun 12 2748 (2021)
  27. Longitudinal relaxation optimized amide 1H-CEST experiments for studying slow chemical exchange processes in fully protonated proteins. Yuwen T, Kay LE. J Biomol NMR 67 295-307 (2017)
  28. Resolution of Stepwise Cooperativities of Copper Binding by the Homotetrameric Copper-Sensitive Operon Repressor (CsoR): Impact on Structure and Stability. Jacobs AD, Chang FM, Morrison L, Dilger JM, Wysocki VH, Clemmer DE, Giedroc DP. Angew Chem Int Ed Engl 54 12795-12799 (2015)
  29. Structure of a low-population intermediate state in the release of an enzyme product. De Simone A, Aprile FA, Dhulesia A, Dobson CM, Vendruscolo M. Elife 4 (2015)
  30. Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces. Louet M, Seifert C, Hensen U, Gräter F. PLoS Comput Biol 11 e1004358 (2015)
  31. Dual Function of Phosphoubiquitin in E3 Activation of Parkin. Walinda E, Morimoto D, Sugase K, Shirakawa M. J Biol Chem 291 16879-16891 (2016)
  32. Enzymes at work are enzymes in motion. Saleh T, Kalodimos CG. Science 355 247-248 (2017)
  33. Orchestrated Domain Movement in Catalysis by Cytochrome P450 Reductase. Freeman SL, Martel A, Raven EL, Roberts GCK. Sci Rep 7 9741 (2017)
  34. ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy. Olivieri C, Li GC, Wang Y, V S M, Walker C, Kim J, Camilloni C, De Simone A, Vendruscolo M, Bernlohr DA, Taylor SS, Veglia G. Sci Adv 8 eabo0696 (2022)
  35. Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A. Juárez-Jiménez J, Gupta AA, Karunanithy G, Mey ASJS, Georgiou C, Ioannidis H, De Simone A, Barlow PN, Hulme AN, Walkinshaw MD, Baldwin AJ, Michel J. Chem Sci 11 2670-2680 (2020)
  36. Mapping the Hydrogen Bond Networks in the Catalytic Subunit of Protein Kinase A Using H/D Fractionation Factors. Li GC, Srivastava AK, Kim J, Taylor SS, Veglia G. Biochemistry 54 4042-4049 (2015)
  37. pH-dependent transient conformational states control optical properties in cyan fluorescent protein. Laricheva EN, Goh GB, Dickson A, Brooks CL. J Am Chem Soc 137 2892-2900 (2015)
  38. Structural basis for cross-reactivity and conformation fluctuation of the major beech pollen allergen Fag s 1. Moraes AH, Asam C, Almeida FCL, Wallner M, Ferreira F, Valente AP. Sci Rep 8 10512 (2018)
  39. The role of slow and fast protein motions in allosteric interactions. Tzeng SR, Kalodimos CG. Biophys Rev 7 251-255 (2015)
  40. Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state. Calligari P, Santucci V, Stella L, Bocchinfuso G. Comput Struct Biotechnol J 19 6125-6139 (2021)
  41. Mechanism of biological denitrification inhibition: procyanidins induce an allosteric transition of the membrane-bound nitrate reductase through membrane alteration. Bardon C, Poly F, Piola F, Pancton M, Comte G, Meiffren G, Haichar Fel Z. FEMS Microbiol Ecol 92 fiw034 (2016)
  42. Role of allosteric switches and adaptor domains in long-distance cross-talk and transient tunnel formation. Sharma N, Ahalawat N, Sandhu P, Strauss E, Mondal J, Anand R. Sci Adv 6 eaay7919 (2020)
  43. Site-directed spin label electron paramagnetic resonance spectroscopy as a probe of conformational dynamics in the Fe(III) "locked-off" state of the CO-sensing transcription factor CooA. Hines JP, Dent MR, Stevens DJ, Burstyn JN. Protein Sci 27 1670-1679 (2018)
  44. The role of surface electrostatics on the stability, function and regulation of human cystathionine β-synthase, a complex multidomain and oligomeric protein. Pey AL, Majtan T, Kraus JP. Biochim Biophys Acta 1844 1453-1462 (2014)
  45. Nitrosative stress sensing in Porphyromonas gingivalis: structure of and heme binding by the transcriptional regulator HcpR. Belvin BR, Musayev FN, Burgner J, Scarsdale JN, Escalante CR, Lewis JP. Acta Crystallogr D Struct Biol 75 437-450 (2019)
  46. Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorγ. Chebaro Y, Sirigu S, Amal I, Lutzing R, Stote RH, Rochette-Egly C, Rochel N, Dejaegere A. PLoS One 12 e0171043 (2017)
  47. Elucidating the mechanisms underlying protein conformational switching using NMR spectroscopy. Jain S, Sekhar A. J Magn Reson Open 10-11 100034 (2022)
  48. Comparative Study NMR Technology: The competitive world of RAS biology. Luchinat C, Parigi G, Ravera E. Nat Chem Biol 10 173-174 (2014)
  49. Protein dynamics: Catch them if you can. Veglia G. Nat Chem Biol 9 410-411 (2013)
  50. NMR illuminates the pathways to ALS. Xie T, Kalodimos CG. Elife 4 e08679 (2015)


Quick links