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Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.

Edink E, Rucktooa P, Retra K, Akdemir A, Nahar T, Zuiderveld O, van Elk R, Janssen E, van Nierop P, van Muijlwijk-Koezen J, Smit AB, Sixma TK, Leurs R, de Esch IJ
J Am Chem Soc 133 5363-71 (2011)
Related entries: 2y54, 2y57, 2y58

Cited: 28 times
EuropePMC logo PMID: 21322593

Abstract

Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand-inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches.

Reviews - 2y56 mentioned but not cited (1)

  1. Size matters in activation/inhibition of ligand-gated ion channels. Du J, Dong H, Zhou HX. Trends Pharmacol Sci 33 482-493 (2012)


Reviews citing this publication (8)

  1. Structural insights into Cys-loop receptor function and ligand recognition. Nys M, Kesters D, Ulens C. Biochem Pharmacol 86 1042-1053 (2013)
  2. 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)
  3. Antibody-enabled small-molecule drug discovery. Lawson AD. Nat Rev Drug Discov 11 519-525 (2012)
  4. A look at ligand binding thermodynamics in drug discovery. Claveria-Gimeno R, Vega S, Abian O, Velazquez-Campoy A. Expert Opin Drug Discov 12 363-377 (2017)
  5. Applications of isothermal titration calorimetry - the research and technical developments from 2011 to 2015. Falconer RJ. J Mol Recognit 29 504-515 (2016)
  6. Structural Studies of Nicotinic Acetylcholine Receptors: Using Acetylcholine-Binding Protein as a Structural Surrogate. Shahsavar A, Gajhede M, Kastrup JS, Balle T. Basic Clin Pharmacol Toxicol 118 399-407 (2016)
  7. Protein crystallography and fragment-based drug design. Caliandro R, Belviso DB, Aresta BM, de Candia M, Altomare CD. Future Med Chem 5 1121-1140 (2013)
  8. Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization. Minetti CA, Remeta DP. Life (Basel) 12 1438 (2022)

Articles citing this publication (19)

  1. Molecular actions of smoking cessation drugs at α4β2 nicotinic receptors defined in crystal structures of a homologous binding protein. Billen B, Spurny R, Brams M, van Elk R, Valera-Kummer S, Yakel JL, Voets T, Bertrand D, Smit AB, Ulens C. Proc Natl Acad Sci U S A 109 9173-9178 (2012)
  2. Application of fragment screening and merging to the discovery of inhibitors of the Mycobacterium tuberculosis cytochrome P450 CYP121. Hudson SA, McLean KJ, Surade S, Yang YQ, Leys D, Ciulli A, Munro AW, Abell C. Angew Chem Int Ed Engl 51 9311-9316 (2012)
  3. Structural characterization of binding mode of smoking cessation drugs to nicotinic acetylcholine receptors through study of ligand complexes with acetylcholine-binding protein. Rucktooa P, Haseler CA, van Elk R, Smit AB, Gallagher T, Sixma TK. J Biol Chem 287 23283-23293 (2012)
  4. Assembly of a π-π stack of ligands in the binding site of an acetylcholine-binding protein. Stornaiuolo M, De Kloe GE, Rucktooa P, Fish A, van Elk R, Edink ES, Bertrand D, Smit AB, de Esch IJ, Sixma TK. Nat Commun 4 1875 (2013)
  5. Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α1(2)βγδ nAChRs. Bourne Y, Sulzenbacher G, Radić Z, Aráoz R, Reynaud M, Benoit E, Zakarian A, Servent D, Molgó J, Taylor P, Marchot P. Structure 23 1106-1115 (2015)
  6. Overcoming the limitations of fragment merging: rescuing a strained merged fragment series targeting Mycobacterium tuberculosis CYP121. Hudson SA, Surade S, Coyne AG, McLean KJ, Leys D, Munro AW, Abell C. ChemMedChem 8 1451-1456 (2013)
  7. Comparative study of flavins binding with human serum albumin: a fluorometric, thermodynamic, and molecular dynamics approach. Sengupta A, Sasikala WD, Mukherjee A, Hazra P. Chemphyschem 13 2142-2153 (2012)
  8. Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to α4β2-nicotinic acetylcholine receptors: an integrated approach to behaviorally active nicotinic ligands. Zhang HK, Eaton JB, Yu LF, Nys M, Mazzolari A, van Elk R, Smit AB, Alexandrov V, Hanania T, Sabath E, Fedolak A, Brunner D, Lukas RJ, Vistoli G, Ulens C, Kozikowski AP. J Med Chem 55 8028-8037 (2012)
  9. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design. Chandramohan A, Krishnamurthy S, Krishnamurthy S, Larsson A, Nordlund P, Jansson A, Anand GS. PLoS Comput Biol 12 e1004840 (2016)
  10. Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators. Ahmad MF, Huff SE, Pink J, Alam I, Zhang A, Perry K, Harris ME, Misko T, Porwal SK, Oleinick NL, Miyagi M, Viswanathan R, Dealwis CG. J Med Chem 58 9498-9509 (2015)
  11. Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics. Mohammad Hosseini Naveh Z, Malliavin TE, Maragliano L, Cottone G, Ciccotti G. PLoS One 9 e88555 (2014)
  12. The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site. Claveria-Gimeno R, Lanuza PM, Morales-Chueca I, Jorge-Torres OC, Vega S, Abian O, Esteller M, Velazquez-Campoy A. Sci Rep 7 41635 (2017)
  13. A Structural Model of the Human α7 Nicotinic Receptor in an Open Conformation. Chiodo L, Malliavin TE, Maragliano L, Cottone G, Ciccotti G. PLoS One 10 e0133011 (2015)
  14. Analytical workflow for rapid screening and purification of bioactives from venom proteomes. Otvos RA, Heus F, Vonk FJ, Halff J, Bruyneel B, Paliukhovich I, Smit AB, Niessen WM, Kool J. Toxicon 76 270-281 (2013)
  15. Miniaturized bioaffinity assessment coupled to mass spectrometry for guided purification of bioactives from toad and cone snail. Heus F, Otvos RA, Aspers RL, van Elk R, Halff JI, Ehlers AW, Dutertre S, Lewis RJ, Wijmenga S, Smit AB, Niessen WM, Kool J. Biology (Basel) 3 139-156 (2014)
  16. Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin. Mondal M, Unver MY, Pal A, Bakker M, Berrier SP, Hirsch AK. Chemistry 22 14826-14830 (2016)
  17. Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition. Kulp JL, Cloudsdale IS, Kulp JL, Guarnieri F. PLoS One 12 e0183327 (2017)
  18. Real-Time Cellular Thermal Shift Assay to Monitor Target Engagement. Sanchez TW, Ronzetti MH, Owens AE, Antony M, Voss T, Wallgren E, Talley D, Balakrishnan K, Leyes Porello SE, Rai G, Marugan JJ, Michael SG, Baljinnyam B, Southall N, Simeonov A, Henderson MJ. ACS Chem Biol 17 2471-2482 (2022)
  19. Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search. Wills S, Sanchez-Garcia R, Dudgeon T, Roughley SD, Merritt A, Hubbard RE, Davidson J, von Delft F, Deane CM. J Chem Inf Model 63 3423-3437 (2023)


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