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PDBsum entry 1p0i

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Hydrolase PDB id
1p0i
Jmol
Contents
Protein chain
523 a.a. *
Ligands
NAG-NAG-FUC ×2
NAG ×3
SO4 ×2
BUA
MES
GOL ×3
Metals
_CL ×2
Waters ×483
* Residue conservation analysis
PDB id:
1p0i
Name: Hydrolase
Title: Crystal structure of human butyryl cholinesterase
Structure: Cholinesterase. Chain: a. Synonym: acylcholine acylhydrolase, choline esterase ii, butyrylcholine esterase, pseudocholinesterase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bche or che1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: ovary cells
Resolution:
2.00Å     R-factor:   0.195     R-free:   0.225
Authors: Y.Nicolet,O.Lockridge,P.Masson,J.C.Fontecilla-Camps,F.Nachon
Key ref:
Y.Nicolet et al. (2003). Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J Biol Chem, 278, 41141-41147. PubMed id: 12869558 DOI: 10.1074/jbc.M210241200
Date:
10-Apr-03     Release date:   05-Aug-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06276  (CHLE_HUMAN) -  Cholinesterase
Seq:
Struc:
 
Seq:
Struc:
602 a.a.
523 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.8  - Cholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acylcholine + H2O = choline + a carboxylate
acylcholine
Bound ligand (Het Group name = MES)
matches with 46.67% similarity
+ H(2)O
= choline
+
carboxylate
Bound ligand (Het Group name = BUA)
matches with 42.86% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   7 terms 
  Biological process     response to drug   13 terms 
  Biochemical function     catalytic activity     9 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M210241200 J Biol Chem 278:41141-41147 (2003)
PubMed id: 12869558  
 
 
Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products.
Y.Nicolet, O.Lockridge, P.Masson, J.C.Fontecilla-Camps, F.Nachon.
 
  ABSTRACT  
 
Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser(198) has been modeled as bound butyrate.
 
  Selected figure(s)  
 
Figure 3.
FIG. 3. Difference Fourier electron density maps for bonded and non-bonded butyrate. a, tetrahedral model. Despite the restrains applied the C-O distance is 1.47 Å, and there is a residual negative electron density peak at -5.7 between these two atoms. The average B-factor for the buryrate moiety is 44 Å2 and that of the tetrahedral C atom is 51.1 Å2 (comparable values for the model with a 2.16-Å-long C-O bond depicted in Fig. 2 are 41.7 and 41.4 Å, respectively). b, non-bonded butyrate model. The C-O distance refines to 2.6 Å, and there is a negative peak at -3.7 below the carboxylate carbon atom. The average B-factor for the buryrate moiety is 41.7 Å2 and that of the carboxylate carbon atom is 45.8 Å2.
Figure 5.
FIG. 5. a, stereo view of the active site after soaking one of the original crystals in a 100 mM choline solution. The orientation is the same as in Fig. 2. b, stereo view of the same structure rotated by 90° around an horizontal axis relative to a. The catalytic serine side chain adopts two different conformations: one where the O interacts with His438 and the other where it replaces a water molecule that interacted with the main chain nitrogen of Ala^199, in the oxyanion hole. c, stereo view of the active site of the soman-aged butyrylthiocholine-BChE complex oriented as in Fig. 1. The 2.3-Å resolution difference Fourier omit map is depicted in green. The covalently bound methylphosphonyl moiety occupies the same position as in soman-aged TcAChE (35). As expected, the quaternary ammonium group of butyrylthiocholine is located in the -cation site, but the substrate adopts a non-productive orientation (see "Results"). The omit Fourier electron density maps show that choline and butyrylthiocholine occupy very similar positions and that the alcohol function of the former and the carbonyl oxygen of the latter establish hydrogen bonds with equivalent water molecules. In all three panels the omit maps are depicted in green and are contoured at a 3 level.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 41141-41147) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20946535 A.Weber, H.Butterweck, U.Mais-Paul, W.Teschner, L.Lei, E.M.Muchitsch, D.Kolarich, F.Altmann, H.J.Ehrlich, and H.P.Schwarz (2011).
Biochemical, molecular and preclinical characterization of a double-virus-reduced human butyrylcholinesterase preparation designed for clinical use.
  Vox Sang, 100, 285-297.  
21091433 F.Nachon, E.Carletti, M.Wandhammer, Y.Nicolet, L.M.Schopfer, P.Masson, and O.Lockridge (2011).
X-ray crystallographic snapshots of reaction intermediates in the G117H mutant of human butyrylcholinesterase, a nerve agent target engineered into a catalytic bioscavenger.
  Biochem J, 434, 73-82.
PDB codes: 2xmb 2xmc 2xmd 2xmg
21364766 L.Pezzementi, F.Nachon, and A.Chatonnet (2011).
Evolution of Acetylcholinesterase and Butyrylcholinesterase in the Vertebrates: An Atypical Butyrylcholinesterase from the Medaka Oryzias latipes.
  PLoS One, 6, e17396.  
21504805 L.Wang, D.Du, D.Lu, C.T.Lin, J.N.Smith, C.Timchalk, F.Liu, J.Wang, and Y.Lin (2011).
Enzyme-linked immunosorbent assay for detection of organophosphorylated butyrylcholinesterase: A biomarker of exposure to organophosphate agents.
  Anal Chim Acta, 693, 1-6.  
21064131 M.Amitay, and A.Shurki (2011).
Hydrolysis of organophosphate compounds by mutant butyrylcholinesterase: a story of two histidines.
  Proteins, 79, 352-364.  
21397501 M.Komloova, K.Musilek, A.Horova, O.Holas, V.Dohnal, F.Gunn-Moore, and K.Kuca (2011).
Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment.
  Bioorg Med Chem Lett, 21, 2505-2509.  
20060815 A.Gaydess, E.Duysen, Y.Li, V.Gilman, A.Kabanov, O.Lockridge, and T.Bronich (2010).
Visualization of exogenous delivery of nanoformulated butyrylcholinesterase to the central nervous system.
  Chem Biol Interact, 187, 295-298.  
20004171 P.Masson, and O.Lockridge (2010).
Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior.
  Arch Biochem Biophys, 494, 107-120.  
  20550720 Z.Ul-Haq, W.Khan, S.Kalsoom, and F.L.Ansari (2010).
In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of beta-amyloid plaques associated with Alzheimer's disease.
  Theor Biol Med Model, 7, 22.  
19368529 E.Carletti, N.Aurbek, E.Gillon, M.Loiodice, Y.Nicolet, J.C.Fontecilla-Camps, P.Masson, H.Thiermann, F.Nachon, and F.Worek (2009).
Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.
  Biochem J, 421, 97.
PDB codes: 2wid 2wif 2wig 2wij 2wik 2wil 2wsl
19383604 E.Podoly, D.E.Shalev, S.Shenhar-Tsarfaty, E.R.Bennett, E.Ben Assayag, H.Wilgus, O.Livnah, and H.Soreq (2009).
The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology.
  J Biol Chem, 284, 17170-17179.  
19217865 F.Gabel, P.Masson, M.T.Froment, B.P.Doctor, A.Saxena, I.Silman, G.Zaccai, and M.Weik (2009).
Direct correlation between molecular dynamics and enzymatic stability: a comparative neutron scattering study of native human butyrylcholinesterase and its "aged" soman conjugate.
  Biophys J, 96, 1489-1494.  
19699221 J.Shenouda, P.Green, and L.Sultatos (2009).
An evaluation of the inhibition of human butyrylcholinesterase and acetylcholinesterase by the organophosphate chlorpyrifos oxon.
  Toxicol Appl Pharmacol, 241, 135-142.  
19452557 M.Amitay, and A.Shurki (2009).
The structure of G117H mutant of butyrylcholinesterase: nerve agents scavenger.
  Proteins, 77, 370-377.  
19292875 M.F.Montenegro, M.T.Moral-Naranjo, E.Muñoz-Delgado, F.J.Campoy, and C.J.Vidal (2009).
Hydrolysis of acetylthiocoline, o-nitroacetanilide and o-nitrotrifluoroacetanilide by fetal bovine serum acetylcholinesterase.
  FEBS J, 276, 2074-2083.  
19715346 N.H.Barakat, X.Zheng, C.B.Gilley, M.MacDonald, K.Okolotowicz, J.R.Cashman, S.Vyas, J.M.Beck, C.M.Hadad, and J.Zhang (2009).
Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.
  Chem Res Toxicol, 22, 1669-1679.  
19493341 P.B.Juhl, P.Trodler, S.Tyagi, and J.Pleiss (2009).
Modelling substrate specificity and enantioselectivity for lipases and esterases by substrate-imprinted docking.
  BMC Struct Biol, 9, 39.  
19827033 S.Y.Chiou, C.F.Huang, M.T.Hwang, and G.Lin (2009).
Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene-di-N-substituted carbamates.
  J Biochem Mol Toxicol, 23, 303-308.  
19254552 W.Yang, Y.Pan, F.Zheng, H.Cho, H.H.Tai, and C.G.Zhan (2009).
Free-energy perturbation simulation on transition states and redesign of butyrylcholinesterase.
  Biophys J, 96, 1931-1938.  
19402731 Y.Pan, J.L.Muzyka, and C.G.Zhan (2009).
Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation.
  J Phys Chem B, 113, 6543-6552.  
18279391 A.Frederick, I.Tsigelny, F.Cohenour, C.Spiker, E.Krejci, A.Chatonnet, S.Bourgoin, G.Richards, T.Allen, M.H.Whitlock, and L.Pezzementi (2008).
Acetylcholinesterase from the invertebrate Ciona intestinalis is capable of assembling into asymmetric forms when co-expressed with vertebrate collagenic tail peptide.
  FEBS J, 275, 1309-1322.  
18429606 E.V.Radchenko, G.F.Makhaeva, V.V.Malygin, V.B.Sokolov, V.A.Palyulin, and N.S.Zefirov (2008).
Modeling of the relationships between the structure of O-phosphorylated oximes and their anticholinesterase activity and selectivity using molecular field topology analysis (MFTA).
  Dokl Biochem Biophys, 418, 47-51.  
18710224 F.Zheng, W.Yang, M.C.Ko, J.Liu, H.Cho, D.Gao, M.Tong, H.H.Tai, J.H.Woods, and C.G.Zhan (2008).
Most efficient cocaine hydrolase designed by virtual screening of transition states.
  J Am Chem Soc, 130, 12148-12155.  
18701720 J.P.Colletier, D.Bourgeois, B.Sanson, D.Fournier, J.L.Sussman, I.Silman, and M.Weik (2008).
Shoot-and-Trap: use of specific x-ray damage to study structural protein dynamics by temperature-controlled cryo-crystallography.
  Proc Natl Acad Sci U S A, 105, 11742-11747.
PDB codes: 2vja 2vjb 2vjc 2vjd 2vt6 2vt7
18208347 M.F.Montenegro, T.M.María, M.P.de la Cadena, F.J.Campoy, E.Muñoz-Delgado, and C.J.Vidal (2008).
Human butyrylcholinesterase components differ in aryl acylamidase activity.
  Biol Chem, 389, 425-432.  
18422653 P.Masson, M.T.Froment, E.Gillon, F.Nachon, O.Lockridge, and L.M.Schopfer (2008).
Kinetic analysis of effector modulation of butyrylcholinesterase-catalysed hydrolysis of acetanilides and homologous esters.
  FEBS J, 275, 2617-2631.  
18563305 S.Y.Chiou, Y.G.Wu, and G.Lin (2008).
Activation mechanisms of butyrylcholinesterase by 2,4,6-trinitrotoluene, 3,3-dimethylbutyl-N-n-butylcarbamate, and 2-trimethylsilyl-ethyl-N-n-butylcarbamate.
  Appl Biochem Biotechnol, 150, 337-344.  
17700357 L.R.Mikami, S.Wieseler, R.L.Souza, L.M.Schopfer, O.Lockridge, and E.A.Chautard-Freire-Maia (2007).
Expression of three naturally occurring genetic variants (G75R, E90D, I99M) of the BCHE gene of human butyrylcholinesterase.
  Pharmacogenet Genomics, 17, 681-685.  
17994573 M.C.Lin, M.T.Hwang, H.G.Chang, C.S.Lin, and G.Lin (2007).
Benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates as conformationally constrained inhibitors of acetylcholinesterase.
  J Biochem Mol Toxicol, 21, 348-353.  
17355286 M.F.Frasco, J.P.Colletier, M.Weik, F.Carvalho, L.Guilhermino, J.Stojan, and D.Fournier (2007).
Mechanisms of cholinesterase inhibition by inorganic mercury.
  FEBS J, 274, 1849-1861.
PDB code: 2j4c
  17768338 M.N.Ngamelue, K.Homma, O.Lockridge, and O.A.Asojo (2007).
Crystallization and X-ray structure of full-length recombinant human butyrylcholinesterase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 723-727.
PDB code: 2pm8
16955366 S.Darvesh, R.Walsh, and E.Martin (2007).
Homocysteine thiolactone and human cholinesterases.
  Cell Mol Neurobiol, 27, 33-48.  
17927177 Y.Pan, D.Gao, W.Yang, H.Cho, and C.G.Zhan (2007).
Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants.
  J Am Chem Soc, 129, 13537-13543.  
16639719 B.M.Liederer, and R.T.Borchardt (2006).
Enzymes involved in the bioconversion of ester-based prodrugs.
  J Pharm Sci, 95, 1177-1195.  
16288482 D.Gao, and C.G.Zhan (2006).
Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase.
  Proteins, 62, 99.  
16342323 D.Rochu, C.Cléry-Barraud, F.Renault, A.Chevalier, C.Bon, and P.Masson (2006).
Capillary electrophoresis versus differential scanning calorimetry for the analysis of free enzyme versus enzyme-ligand complexes: in the search of the ligand-free status of cholinesterases.
  Electrophoresis, 27, 442-451.  
16865342 I.Gazić, A.Bosak, G.Sinko, V.Vinković, and Z.Kovarik (2006).
Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases.
  Anal Bioanal Chem, 385, 1513-1519.  
16763558 J.P.Colletier, D.Fournier, H.M.Greenblatt, J.Stojan, J.L.Sussman, G.Zaccai, I.Silman, and M.Weik (2006).
Structural insights into substrate traffic and inhibition in acetylcholinesterase.
  EMBO J, 25, 2746-2756.
PDB codes: 2c4h 2c58 2c5f 2c5g
16572227 P.J.Houghton, Y.Ren, and M.J.Howes (2006).
Acetylcholinesterase inhibitors from plants and fungi.
  Nat Prod Rep, 23, 181-199.  
16570913 W.Luo, Q.S.Yu, S.S.Kulkarni, D.A.Parrish, H.W.Holloway, D.Tweedie, A.Shafferman, D.K.Lahiri, A.Brossi, and N.H.Greig (2006).
Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine.
  J Med Chem, 49, 2174-2185.  
17136732 Z.Prokop, F.Oplustil, J.DeFrank, and J.Damborský (2006).
Enzymes fight chemical weapons.
  Biotechnol J, 1, 1370-1380.  
16851561 A.Hamza, H.Cho, H.H.Tai, and C.G.Zhan (2005).
Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants.
  J Phys Chem B, 109, 4776-4782.  
16319079 C.G.Zhan, and D.Gao (2005).
Catalytic mechanism and energy barriers for butyrylcholinesterase-catalyzed hydrolysis of cocaine.
  Biophys J, 89, 3863-3872.  
15696543 D.Suárez, and M.J.Field (2005).
Molecular dynamics simulations of human butyrylcholinesterase.
  Proteins, 59, 104-117.  
16100272 F.Gabel, M.Weik, P.Masson, F.Renault, D.Fournier, L.Brochier, B.P.Doctor, A.Saxena, I.Silman, and G.Zaccai (2005).
Effects of soman inhibition and of structural differences on cholinesterase molecular dynamics: a neutron scattering study.
  Biophys J, 89, 3303-3311.  
16183292 M.I.Rodríguez-Franco, M.I.Fernández-Bachiller, C.Pérez, A.Castro, and A.Martínez (2005).
Design and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase.
  Bioorg Med Chem, 13, 6795-6802.  
  16788731 O.Lockridge, L.M.Schopfer, G.Winger, and J.H.Woods (2005).
LARGE SCALE PURIFICATION OF BUTYRYLCHOLINESTERASE FROM HUMAN PLASMA SUITABLE FOR INJECTION INTO MONKEYS; A POTENTIAL NEW THERAPEUTIC FOR PROTECTION AGAINST COCAINE AND NERVE AGENT TOXICITY.
  J Med Chem Biol Radiol Def, 3, nihms5095.  
15582466 S.Darvesh, R.S.McDonald, A.Penwell, S.Conrad, K.V.Darvesh, D.Mataija, G.Gomez, A.Caines, R.Walsh, and E.Martin (2005).
Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives.
  Bioorg Med Chem, 13, 211-222.  
16275916 Y.Pan, D.Gao, W.Yang, H.Cho, G.Yang, H.H.Tai, and C.G.Zhan (2005).
Computational redesign of human butyrylcholinesterase for anticocaine medication.
  Proc Natl Acad Sci U S A, 102, 16656-16661.  
15272157 A.W.Schüttelkopf, and D.M.van Aalten (2004).
PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.
  Acta Crystallogr D Biol Crystallogr, 60, 1355-1363.  
15111428 F.Gabel, M.Weik, B.P.Doctor, A.Saxena, D.Fournier, L.Brochier, F.Renault, P.Masson, I.Silman, and G.Zaccai (2004).
The influence of solvent composition on global dynamics of human butyrylcholinesterase powders: a neutron-scattering study.
  Biophys J, 86, 3152-3165.  
15030487 J.Stojan, L.Brochier, C.Alies, J.P.Colletier, and D.Fournier (2004).
Inhibition of Drosophila melanogaster acetylcholinesterase by high concentrations of substrate.
  Eur J Biochem, 271, 1364-1371.  
15111430 M.Weik, X.Vernede, A.Royant, and D.Bourgeois (2004).
Temperature derivative fluorescence spectroscopy as a tool to study dynamical changes in protein crystals.
  Biophys J, 86, 3176-3185.  
14686935 P.Masson, B.N.Goldstein, J.C.Debouzy, M.T.Froment, O.Lockridge, and L.M.Schopfer (2004).
Damped oscillatory hysteretic behaviour of butyrylcholinesterase with benzoylcholine as substrate.
  Eur J Biochem, 271, 220-234.  
15128307 P.Masson, N.Bec, M.T.Froment, F.Nachon, C.Balny, O.Lockridge, and L.M.Schopfer (2004).
Rate-determining step of butyrylcholinesterase-catalyzed hydrolysis of benzoylcholine and benzoylthiocholine. Volumetric study of wild-type and D70G mutant behavior.
  Eur J Biochem, 271, 1980-1990.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.