PDBsum entry 1ehq

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Hydrolase PDB id
Protein chain
526 a.a.
Theoretical model
PDB id:
Name: Hydrolase
Title: Model of (+)-cocaine-bound bche complex
Structure: Butyrylcholine esterase. Chain: a. Ec:
Source: Homo sapiens. Human
Authors: H.Sun,J.El Yazal,W.S.Brimijoin,Y.P.Pang
Key ref:
H.Sun et al. (2001). Predicted Michaelis-Menten complexes of cocaine-butyrylcholinesterase. Engineering effective butyrylcholinesterase mutants for cocaine detoxication. J Biol Chem, 276, 9330-9336. PubMed id: 11104759 DOI: 10.1074/jbc.M006676200
22-Feb-00     Release date:   08-Aug-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P06276  (CHLE_HUMAN) -  Cholinesterase
602 a.a.
526 a.a.*
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Cholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acylcholine + H2O = choline + a carboxylate
+ H(2)O
= choline
+ carboxylate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1074/jbc.M006676200 J Biol Chem 276:9330-9336 (2001)
PubMed id: 11104759  
Predicted Michaelis-Menten complexes of cocaine-butyrylcholinesterase. Engineering effective butyrylcholinesterase mutants for cocaine detoxication.
H.Sun, J.El Yazal, O.Lockridge, L.M.Schopfer, S.Brimijoin, Y.P.Pang.
Butyrylcholinesterase (BChE) is important in cocaine metabolism, but it hydrolyzes (-)-cocaine only one-two thousandth as fast as the unnatural (+)-stereoisomer. A starting point in engineering BChE mutants that rapidly clear cocaine from the bloodstream, for overdose treatment, is to elucidate structural factors underlying the stereochemical difference in catalysis. Here, we report two three-dimensional Michaelis-Menten complexes of BChE liganded with natural and unnatural cocaine molecules, respectively, that were derived from molecular modeling and supported by experimental studies. Such complexes revealed that the benzoic ester group of both cocaine stereoisomers must rotate toward the catalytic Ser(198) for hydrolysis. Rotation of (-)-cocaine appears to be hindered by interactions of its phenyl ring with Phe(329) and Trp(430). These interactions do not occur with (+)-cocaine. Because the rate of (-)-cocaine hydrolysis is predicted to be determined mainly by the re-orientation step, it should not be greatly influenced by pH. In fact, measured rates of this reaction were nearly constant over the pH range from 5.5 to 8.5, despite large rate changes in hydrolysis of (+)-cocaine. Our models can explain why BChE hydrolyzes (+)-cocaine faster than (-)-cocaine, and they suggest that mutations of certain residues in the catalytic site could greatly improve catalytic efficiency and the potential for detoxication.
  Selected figure(s)  
Figure 1.
Fig. 1. The natural (top) and synthetic (bottom) cocaine structures and definitions of five rotatable torsions used in the conformational search.
Figure 4.
Fig. 4. Close-up view of the active sites of the time-averaged ()-cocaine-BChE (top) and (+)-cocaine-BChE (bottom) complexes derived from 1.0-ns MD simulations (perspective looking down into the active site of BChE). Hydrogen atoms are not displayed, for clarity. The carbonyl carbon atoms and the hydroxyl oxygen atom are represented in a ball model.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 9330-9336) copyright 2001.  
  Figures were selected by the author.  
    Author's comment    
  For the validation of these models (PDB codes: 1eho, 1ehq and 1kcj) see the following references:
Sun H, Pang YP, Lockridge O, Brimijoin S (2002). Re-engineering butyrylcholinesterase as a cocaine hydrolase. Mol. Pharmacol., 62, 220-224. [PubMed: 12130672]
Sun H, Shen ML, Pang YP, Lockridge O, Brimijoin S (2002). Cocaine metabolism accelerated by a re-engineered human butyrylcholinesterase. J. Pharmacol. Exp. Ther., 302, 710-716. [PubMed: 12130735]

Literature references that cite this PDB file's key reference

  PubMed id Reference
20972552 M.E.Carroll, Y.Gao, S.Brimijoin, and J.J.Anker (2011).
Effects of cocaine hydrolase on cocaine self-administration under a PR schedule and during extended access (escalation) in rats.
  Psychopharmacology (Berl), 213, 817-829.  
19536291 F.Ekström, A.Hörnberg, E.Artursson, L.G.Hammarström, G.Schneider, and Y.P.Pang (2009).
Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.
  PLoS One, 4, e5957.
PDB codes: 2whp 2whq 2whr
  20161378 F.Zheng, and C.G.Zhan (2009).
Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anticocaine medications.
  Future Med Chem, 1, 515-528.  
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.  
19478136 Y.Gao, and S.Brimijoin (2009).
Lasting reduction of cocaine action in neostriatum--a hydrolase gene therapy approach.
  J Pharmacol Exp Ther, 330, 449-457.  
17989928 F.Zheng, and C.G.Zhan (2008).
Rational design of an enzyme mutant for anti-cocaine therapeutics.
  J Comput Aided Mol Des, 22, 661-671.  
18292872 F.Zheng, and C.G.Zhan (2008).
Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction.
  Org Biomol Chem, 6, 836-843.  
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.  
18199998 S.Brimijoin, Y.Gao, J.J.Anker, L.A.Gliddon, D.Lafleur, R.Shah, Q.Zhao, M.Singh, and M.E.Carroll (2008).
A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats.
  Neuropsychopharmacology, 33, 2715-2725.  
18514640 Y.Gao, D.LaFleur, R.Shah, Q.Zhao, M.Singh, and S.Brimijoin (2008).
An albumin-butyrylcholinesterase for cocaine toxicity and addiction: catalytic and pharmacokinetic properties.
  Chem Biol Interact, 175, 83-87.  
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.  
16355430 D.Gao, H.Cho, W.Yang, Y.Pan, G.Yang, H.H.Tai, and C.G.Zhan (2006).
Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition-state simulation.
  Angew Chem Int Ed Engl, 45, 653-657.  
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.  
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.  
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.  
15308216 K.Knösche, J.Halámek, A.Makower, D.Fournier, and F.W.Scheller (2004).
Molecular recognition of cocaine by acetylcholinesterases for affinity purification and bio-sensing.
  Biosens Bioelectron, 20, 153-160.  
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.  
12948782 G.A.Lazar, S.A.Marshall, J.J.Plecs, S.L.Mayo, and J.R.Desjarlais (2003).
Designing proteins for therapeutic applications.
  Curr Opin Struct Biol, 13, 513-518.  
11920879 D.Rochu, F.Renault, and P.Masson (2002).
Detection of unwanted protein-bound ligands by capillary zone electrophoresis: the case of hidden ligands that stabilize cholinesterase conformation.
  Electrophoresis, 23, 930-937.  
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.