1ea5 › Citations

X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement.

Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He XC, Jin GY, Yu GL, Tang XC, Silman I, Bai DL, Sussman JL
Biochemistry 41 10810-8 (2002)
Related entries: 1acj, 1acl, 1gpk, 1gpn

Cited: 84 times
EuropePMC logo PMID: 12196020

Abstract

Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 microM, respectively, compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H.pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral.

Reviews - 1ea5 mentioned but not cited (2)

  1. Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery. Hall DR, Kozakov D, Whitty A, Vajda S. Trends Pharmacol Sci 36 724-736 (2015)
  2. Mining electron density for functionally relevant protein polysterism in crystal structures. Fraser JS, Jackson CJ. Cell Mol Life Sci 68 1829-1841 (2011)

Articles - 1ea5 mentioned but not cited (41)

  1. Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site. Bourne Y, Taylor P, Radić Z, Marchot P. EMBO J 22 1-12 (2003)
  2. THEMATICS: a simple computational predictor of enzyme function from structure. Ondrechen MJ, Clifton JG, Ringe D. Proc Natl Acad Sci U S A 98 12473-12478 (2001)
  3. Structural insights into substrate traffic and inhibition in acetylcholinesterase. Colletier JP, Fournier D, Greenblatt HM, Stojan J, Sussman JL, Zaccai G, Silman I, Weik M. EMBO J 25 2746-2756 (2006)
  4. Evolutionary origin of a secondary structure: π-helices as cryptic but widespread insertional variations of α-helices that enhance protein functionality. Cooley RB, Arp DJ, Karplus PA. J Mol Biol 404 232-246 (2010)
  5. Evidence of introgression of the ace-1(R) mutation and of the ace-1 duplication in West African Anopheles gambiae s. s. Djogbénou L, Chandre F, Berthomieu A, Dabiré R, Koffi A, Alout H, Weill M. PLoS One 3 e2172 (2008)
  6. Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site. Harel M, Sonoda LK, Silman I, Sussman JL, Rosenberry TL. J Am Chem Soc 130 7856-7861 (2008)
  7. Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics. Xu Y, Colletier JP, Weik M, Jiang H, Moult J, Silman I, Sussman JL. Biophys J 95 2500-2511 (2008)
  8. PDBSiteScan: a program for searching for active, binding and posttranslational modification sites in the 3D structures of proteins. Ivanisenko VA, Pintus SS, Grigorovich DA, Kolchanov NA. Nucleic Acids Res 32 W549-54 (2004)
  9. Predicting protein function and binding profile via matching of local evolutionary and geometric surface patterns. Tseng YY, Dundas J, Liang J. J Mol Biol 387 451-464 (2009)
  10. Free energy landscape for the binding process of Huperzine A to acetylcholinesterase. Bai F, Xu Y, Chen J, Liu Q, Gu J, Wang X, Ma J, Li H, Onuchic JN, Jiang H. Proc Natl Acad Sci U S A 110 4273-4278 (2013)
  11. Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations. Sanson B, Colletier JP, Xu Y, Lang PT, Jiang H, Silman I, Sussman JL, Weik M. Protein Sci 20 1114-1118 (2011)
  12. Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design. Xu Y, Colletier JP, Jiang H, Silman I, Sussman JL, Weik M. Protein Sci 17 601-605 (2008)
  13. Evolution of acetylcholinesterase and butyrylcholinesterase in the vertebrates: an atypical butyrylcholinesterase from the Medaka Oryzias latipes. Pezzementi L, Nachon F, Chatonnet A. PLoS One 6 e17396 (2011)
  14. Prediction of Ordered Water Molecules in Protein Binding Sites from Molecular Dynamics Simulations: The Impact of Ligand Binding on Hydration Networks. Rudling A, Orro A, Carlsson J. J Chem Inf Model 58 350-361 (2018)
  15. Utilizing experimental data for reducing ensemble size in flexible-protein docking. Xu M, Lill MA. J Chem Inf Model 52 187-198 (2012)
  16. Specific protein dynamics near the solvent glass transition assayed by radiation-induced structural changes. Weik M, Ravelli RB, Silman I, Sussman JL, Gros P, Kroon J. Protein Sci 10 1953-1961 (2001)
  17. Molecular basis of inhibitory activities of berberine against pathogenic enzymes in Alzheimer's disease. Ji HF, Shen L. ScientificWorldJournal 2012 823201 (2012)
  18. A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations. Bennion BJ, Essiz SG, Lau EY, Fattebert JL, Emigh A, Lightstone FC. PLoS One 10 e0121092 (2015)
  19. BP-Dock: a flexible docking scheme for exploring protein-ligand interactions based on unbound structures. Bolia A, Gerek ZN, Ozkan SB. J Chem Inf Model 54 913-925 (2014)
  20. Electrostatic steering at acetylcholine binding sites. Meltzer RH, Thompson E, Soman KV, Song XZ, Ebalunode JO, Wensel TG, Briggs JM, Pedersen SE. Biophys J 91 1302-1314 (2006)
  21. Monitoring of Target-Site Mutations Conferring Insecticide Resistance in Spodoptera frugiperda. Boaventura D, Martin M, Pozzebon A, Mota-Sanchez D, Nauen R. Insects 11 E545 (2020)
  22. Virtual screening of acetylcholinesterase inhibitors using the Lipinski's rule of five and ZINC databank. Nogara PA, Saraiva Rde A, Caeran Bueno D, Lissner LJ, Lenz Dalla Corte C, Braga MM, Rosemberg DB, Rocha JB. Biomed Res Int 2015 870389 (2015)
  23. The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex. Dym O, Song W, Felder C, Roth E, Shnyrov V, Ashani Y, Xu Y, Joosten RP, Weiner L, Sussman JL, Silman I. Protein Sci 25 1096-1114 (2016)
  24. ACE: an efficient and sensitive tool to detect insecticide resistance-associated mutations in insect acetylcholinesterase from RNA-Seq data. Guo D, Luo J, Zhou Y, Xiao H, He K, Yin C, Xu J, Li F. BMC Bioinformatics 18 330 (2017)
  25. Structural and functional characterization of the interaction of the photosensitizing probe methylene blue with Torpedo californica acetylcholinesterase. Paz A, Roth E, Ashani Y, Xu Y, Shnyrov VL, Sussman JL, Silman I, Weiner L. Protein Sci 21 1138-1152 (2012)
  26. Toxicological and molecular profiling of insecticide resistance in a Brazilian strain of fall armyworm resistant to Bt Cry1 proteins. Boaventura D, Buer B, Hamaekers N, Maiwald F, Nauen R. Pest Manag Sci 77 3713-3726 (2021)
  27. Kinetics of Torpedo californica acetylcholinesterase inhibition by bisnorcymserine and crystal structure of the complex with its leaving group. Bartolucci C, Stojan J, Yu QS, Greig NH, Lamba D. Biochem J 444 269-277 (2012)
  28. Biochemical properties, expression profiles, and tissue localization of orthologous acetylcholinesterase-2 in the mosquito, Anopheles gambiae. Zhao P, Wang Y, Jiang H. Insect Biochem Mol Biol 43 260-271 (2013)
  29. Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations. Cheng S, Song W, Yuan X, Xu Y. Sci Rep 7 3219 (2017)
  30. Molecular characterization of monoclonal antibodies that inhibit acetylcholinesterase by targeting the peripheral site and backdoor region. Bourne Y, Renault L, Essono S, Mondielli G, Lamourette P, Boquet D, Grassi J, Marchot P. PLoS One 8 e77226 (2013)
  31. Quantitative Assessment of Chirality of Protein Secondary Structures and Phenylalanine Peptide Nanotubes. Sidorova A, Bystrov V, Lutsenko A, Shpigun D, Belova E, Likhachev I. Nanomaterials (Basel) 11 3299 (2021)
  32. Dyhidro-β-agarofurans natural and synthetic as acetylcholinesterase and COX inhibitors: interaction with the peripheral anionic site (AChE-PAS), and anti-inflammatory potentials. Alarcón-Enos J, Muñoz-Núñez E, Gutiérrez M, Quiroz-Carreño S, Pastene-Navarrete E, Céspedes Acuña C. J Enzyme Inhib Med Chem 37 1845-1856 (2022)
  33. Torpedo californica acetylcholinesterase is stabilized by binding of a divalent metal ion to a novel and versatile 4D motif. Silman I, Shnyrov VL, Ashani Y, Roth E, Nicolas A, Sussman JL, Weiner L. Protein Sci 30 966-981 (2021)
  34. Kinetic Modeling of Time-Dependent Enzyme Inhibition by Pre-Steady-State Analysis of Progress Curves: The Case Study of the Anti-Alzheimer's Drug Galantamine. Lamba D, Pesaresi A. Int J Mol Sci 23 5072 (2022)
  35. Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors. Raza A, Saeed A, Ibrar A, Muddassar M, Khan AA, Iqbal J. ISRN Pharmacol 2012 707932 (2012)
  36. Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds as Potential Cholinesterases Inhibitors: Synthesis, Enzyme Inhibition Assays, and Molecular Modeling Studies. Rodríguez Núñez YA, Gutíerrez M, Alzate-Morales J, Adasme-Carreño F, Güiza FM, Bernal CC, Bohórquez ARR. Int J Mol Sci 21 E5 (2019)
  37. Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase. Gonzalez J, Ramirez J, Schwans JP. Amino Acids 48 2755-2763 (2016)
  38. Geometry of protein shape and its evolutionary pattern for function prediction and characterization. Liang J. Annu Int Conf IEEE Eng Med Biol Soc 2009 2324-2327 (2009)
  39. Instantaneous generation of protein hydration properties from static structures. Ghanbarpour A, Mahmoud AH, Lill MA. Commun Chem 3 188 (2020)
  40. The Distinctive Permutated Domain Structure of Periplasmic α-Amylase (MalS) from Glycoside Hydrolase Family 13 Subfamily 19. An Y, Tran PL, Yoo MJ, Song HN, Park KH, Kim TJ, Park JT, Woo EJ. Molecules 28 3972 (2023)
  41. Thermal denaturation of wild type and mutant recombinant acetylcholinesterase from amphioxus: effects of the temperature of in vitro expression and of reversible inhibitors. Perrin B, Rowland M, Wolfe M, Tsigelny I, Pezzementi L. Invert Neurosci 8 147-155 (2008)


Reviews citing this publication (8)

  1. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Sharma K. Mol Med Rep 20 1479-1487 (2019)
  2. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Wang R, Yan H, Tang XC. Acta Pharmacol Sin 27 1-26 (2006)
  3. Gates of enzymes. Gora A, Brezovsky J, Damborsky J. Chem Rev 113 5871-5923 (2013)
  4. Huperzine A from Huperzia species--an ethnopharmacolgical review. Ma X, Tan C, Zhu D, Gang DR, Xiao P. J Ethnopharmacol 113 15-34 (2007)
  5. Acetylcholinesterase: a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer's disease. Greenblatt HM, Dvir H, Silman I, Sussman JL. J Mol Neurosci 20 369-383 (2003)
  6. Non-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesterase. Zhang HY, Yan H, Tang XC. Cell Mol Neurobiol 28 173-183 (2008)
  7. Molecular interactions of cholinesterases inhibitors using in silico methods: current status and future prospects. Khan MT. N Biotechnol 25 331-346 (2009)
  8. Natural Products from Plants and Algae for Treatment of Alzheimer's Disease: A Review. Klose J, Griehl C, Roßner S, Schilling S. Biomolecules 12 694 (2022)

Articles citing this publication (33)

  1. Acetylcholinesterase: from 3D structure to function. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Chem Biol Interact 187 10-22 (2010)
  2. Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition. Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR. Chem Biol 10 341-349 (2003)
  3. Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling. Berg L, Andersson CD, Artursson E, Hörnberg A, Tunemalm AK, Linusson A, Ekström F. PLoS One 6 e26039 (2011)
  4. Acetylcholinesterase inhibitory activity of lycopodane-type alkaloids from the Icelandic Lycopodium annotinum ssp. alpestre. Halldorsdottir ES, Jaroszewski JW, Olafsdottir ES. Phytochemistry 71 149-157 (2010)
  5. Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates. Katz FS, Pecic S, Tran TH, Trakht I, Schneider L, Zhu Z, Ton-That L, Luzac M, Zlatanic V, Damera S, Macdonald J, Landry DW, Tong L, Stojanovic MN. Chembiochem 16 2205-2215 (2015)
  6. CH/pi hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase. Umezawa Y, Nishio M. Biopolymers 79 248-258 (2005)
  7. Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer's disease. da Silva CH, Campo VL, Carvalho I, Taft CA. J Mol Graph Model 25 169-175 (2006)
  8. Identification and Expression of Acetylcholinesterase in Octopus vulgaris Arm Development and Regeneration: a Conserved Role for ACHE? Fossati SM, Candiani S, Nödl MT, Maragliano L, Pennuto M, Domingues P, Benfenati F, Pestarino M, Zullo L. Mol Neurobiol 52 45-56 (2015)
  9. Theoretical insights into the mechanism of acetylcholinesterase-catalyzed acylation of acetylcholine. Manojkumar TK, Cui C, Kim KS. J Comput Chem 26 606-611 (2005)
  10. Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer's disease. Pinsetta FR, Taft CA, de Paula da Silva CH. J Biomol Struct Dyn 32 1047-1063 (2014)
  11. Atomic insight into designed carbamate-based derivatives as acetylcholine esterase (AChE) inhibitors: a computational study by multiple molecular docking and molecular dynamics simulation. Mohammadi T, Ghayeb Y. J Biomol Struct Dyn 36 126-138 (2018)
  12. Huperzine A provides neuroprotection against several cell death inducers using in vitro model systems of motor neuron cell death. Hemendinger RA, Armstrong EJ, Persinski R, Todd J, Mougeot JL, Volvovitz F, Rosenfeld J. Neurotox Res 13 49-61 (2008)
  13. Huprines for Alzheimer's disease drug development. Muñoz-Torrero D, Camps P. Expert Opin Drug Discov 3 65-81 (2008)
  14. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals. Amat-Ur-Rasool H, Ahmed M. PLoS One 10 e0136509 (2015)
  15. (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase. Al-Rashid ZF, Hsung RP. Bioorg Med Chem Lett 21 2687-2691 (2011)
  16. Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method. Kitisripanya N, Saparpakorn P, Wolschann P, Hannongbua S. Nanomedicine 7 60-68 (2011)
  17. Study of the interaction of Huperzia saururus Lycopodium alkaloids with the acetylcholinesterase enzyme. Puiatti M, Borioni JL, Vallejo MG, Cabrera JL, Agnese AM, Ortega MG, Pierini AB. J Mol Graph Model 44 136-144 (2013)
  18. Understanding the conformational flexibility and electrostatic properties of curcumin in the active site of rhAChE via molecular docking, molecular dynamics, and charge density analysis. Saravanan K, Kalaiarasi C, Kumaradhas P. J Biomol Struct Dyn 35 3627-3647 (2017)
  19. Virtual screening, molecular interaction field, molecular dynamics, docking, density functional, and ADMET properties of novel AChE inhibitors in Alzheimer's disease. da Silva CH, Carvalho I, Taft CA. J Biomol Struct Dyn 24 515-524 (2007)
  20. Exploring different virtual screening strategies for acetylcholinesterase inhibitors. Mishra N, Basu A. Biomed Res Int 2013 236850 (2013)
  21. Similar but different: thermodynamic and structural characterization of a pair of enantiomers binding to acetylcholinesterase. Berg L, Niemiec MS, Qian W, Andersson CD, Wittung-Stafshede P, Ekström F, Linusson A. Angew Chem Int Ed Engl 51 12716-12720 (2012)
  22. Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors. Shi YF, Zhang HY, Wang W, Fu Y, Xia Y, Tang XC, Bai DL, He XC. Acta Pharmacol Sin 30 1195-1203 (2009)
  23. Selagoline, a new alkaloid from Huperzia selago. Staerk D, Larsen J, Larsen LA, Olafsdottir ES, Witt M, Jaroszewski JW. Nat Prod Res 18 197-203 (2004)
  24. Structure-based virtual screening leading to discovery of highly selective butyrylcholinesterase inhibitors with solanaceous alkaloid scaffolds. Zhou S, Yuan Y, Zheng F, Zhan CG. Chem Biol Interact 308 372-376 (2019)
  25. Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors. de Aquino RA, Modolo LV, Alves RB, de Fátima Â. Org Biomol Chem 11 8395-8409 (2013)
  26. A conformational change in the peripheral anionic site of Torpedo californica acetylcholinesterase induced by a bis-imidazolium oxime. Legler PM, Soojhawon I, Millard CB. Acta Crystallogr D Biol Crystallogr 71 1788-1798 (2015)
  27. Photohuperzine A-A new photoisomer of huperzine A: structure elucidation, formation kinetics and activity assessment. Marques LA, Giera M, de Kanter FJ, Niessen WM, Lingeman H, Irth H. J Pharm Biomed Anal 52 190-194 (2010)
  28. Synthesis and acetylcholinesterase inhibition of derivatives of huperzine B. Feng S, Xia Y, Han D, Zheng C, He X, Tang X, Bai D. Bioorg Med Chem Lett 15 523-526 (2005)
  29. In Silico Design of Beta-Secretase Inhibitors in Alzheimer's Disease. Semighini EP. Chem Biol Drug Des 86 284-290 (2015)
  30. Structure-based, biophysical annotation of molecular coevolution of acetylcholinesterase. Weissgraeber S, Hoffgaard F, Hamacher K. Proteins 79 3144-3154 (2011)
  31. Determination of Multidirectional Pathways for Ligand Release from the Receptor: A New Approach Based on Differential Evolution. Nguyen HL, Thai NQ, Li MS. J Chem Theory Comput 18 3860-3872 (2022)
  32. Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers. Vaaland IC, López Ó, Puerta A, Fernandes MX, Padrón JM, Fernández-Bolaños JG, Sydnes MO, Lindbäck E. J Enzyme Inhib Med Chem 38 349-360 (2023)
  33. Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets. Guo Q, Wu G, Huang F, Wei Z, Wang JZ, Zhang B, Liu R, Yang Y, Wang X, Li HL. Aging (Albany NY) 14 8077-8094 (2022)


Related citations provided by authors (6)

  1. Residues in Torpedo californica acetylcholinesterase necessary for processing to a glycosyl phosphatidylinositol-anchored form.. Bucht G, Hjalmarsson K Biochim Biophys Acta 1292 223-32 (1996)
  2. Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography.. Axelsen PH, Harel M, Silman I, Sussman JL Protein Sci 3 188-97 (1994)
  3. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.. Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL Proc Natl Acad Sci U S A 90 9031-5 (1993)
  4. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein.. Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I Science 253 872-9 (1991)
  5. Purification and crystallization of a dimeric form of acetylcholinesterase from Torpedo californica subsequent to solubilization with phosphatidylinositol-specific phospholipase C.. Sussman JL, Harel M, Frolow F, Varon L, Toker L, Futerman AH, Silman I J Mol Biol 203 821-3 (1988)
  6. Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence.. Schumacher M, Camp S, Maulet Y, Newton M, MacPhee-Quigley K, Taylor SS, Friedmann T, Taylor P Nature 319 407-9

Quick links