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PDBsum entry 1kcj

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Hydrolase PDB id
1kcj
Jmol
Contents
Protein chain
526 a.a.
Ligands
CCA
Theoretical model
PDB id:
1kcj
Name: Hydrolase
Title: Model of (-)-cocaine-bound (-)-cocaine hydrolase complex
Structure: Cholinesterase. Chain: a. Synonym: (-)-cocaine hydrolase. Mutation: yes
Source: Homo sapiens. Human
Authors: H.Sun,Y.-P.Pang,O.Lockridge,S.Brimijoin
Key ref: H.Sun et al. (2002). Re-engineering butyrylcholinesterase as a cocaine hydrolase. Mol Pharmacol, 62, 220-224. PubMed id: 12130672
Date:
08-Nov-01     Release date:   25-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06276  (CHLE_HUMAN) -  Cholinesterase
Seq:
Struc:
 
Seq:
Struc:
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.3.1.1.8  - Cholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acylcholine + H2O = choline + a carboxylate
acylcholine
+ H(2)O
= choline
+ carboxylate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Mol Pharmacol 62:220-224 (2002)
PubMed id: 12130672  
 
 
Re-engineering butyrylcholinesterase as a cocaine hydrolase.
H.Sun, Y.P.Pang, O.Lockridge, S.Brimijoin.
 
  ABSTRACT  
 
To address the problem of acute cocaine overdose, we undertook molecular engineering of butyrylcholinesterase (BChE) as a cocaine hydrolase so that modest doses could be used to accelerate metabolic clearance of this drug. Molecular modeling of BChE complexed with cocaine suggested that the inefficient hydrolysis (k(cat) = 4 min(-1)) involves a rotation toward the catalytic triad, hindered by Tyr332. To eliminate rotational hindrance and retain substrate affinity, we introduced two amino acid substitutions (Ala328Trp/Tyr332Ala). The resulting mutant BChE reduced cocaine burden in tissues, accelerated plasma clearance by 20-fold, and prevented cocaine-induced hyperactivity in mice. The enzyme's kinetic properties (k(cat) = 154 min(-1), K(M) = 18 microM) satisfy criteria suggested previously for treating cocaine overdose (k(cat) >120 min(-1), K(M) < 30 microM). This success demonstrates that computationally guided mutagenesis can generate functionally novel enzymes with clinical potential.
 

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.  
20004171 P.Masson, and O.Lockridge (2010).
Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior.
  Arch Biochem Biophys, 494, 107-120.  
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.  
19642701 J.Liu, A.Hamza, and C.G.Zhan (2009).
Fundamental reaction mechanism and free energy profile for (-)-cocaine hydrolysis catalyzed by cocaine esterase.
  J Am Chem Soc, 131, 11964-11975.  
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.  
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.  
18468882 C.Teller, J.Halámek, J.Zeravík, W.F.Stöcklein, and F.W.Scheller (2008).
Development of a bifunctional sensor using haptenized acetylcholinesterase and application for the detection of cocaine and organophosphates.
  Biosens Bioelectron, 24, 111-117.  
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.  
17565384 Q.Wang, and Y.P.Pang (2007).
Accurate reproduction of 161 small-molecule complex crystal structures using the EUDOC program: expanding the use of EUDOC to supramolecular chemistry.
  PLoS ONE, 2, e531.  
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.  
16519684 A.Hrabovská, J.C.Debouzy, M.T.Froment, F.Devínsky, I.Pauliková, and P.Masson (2006).
Rat butyrylcholinesterase-catalysed hydrolysis of N-alkyl homologues of benzoylcholine.
  FEBS J, 273, 1185-1197.  
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.  
16708286 Y.Gao, and S.Brimijoin (2006).
Viral transduction of cocaine hydrolase in brain reward centers.
  Cell Mol Neurobiol, 26, 357-363.  
16319079 C.G.Zhan, and D.Gao (2005).
Catalytic mechanism and energy barriers for butyrylcholinesterase-catalyzed hydrolysis of cocaine.
  Biophys J, 89, 3863-3872.  
16011362 C.J.Rogers, J.M.Mee, G.F.Kaufmann, T.J.Dickerson, and K.D.Janda (2005).
Toward cocaine esterase therapeutics.
  J Am Chem Soc, 127, 10016-10017.  
  16569291 M.E.Selkirk, O.Lazari, and J.B.Matthews (2005).
Functional genomics of nematode acetylcholinesterases.
  Parasitology, 131, S3-18.  
15952908 T.J.Dickerson, G.F.Kaufmann, and K.D.Janda (2005).
Bacteriophage-mediated protein delivery into the central nervous system and its application in immunopharmacotherapy.
  Expert Opin Biol Ther, 5, 773-781.  
16353936 T.J.Dickerson, and K.D.Janda (2005).
Recent advances for the treatment of cocaine abuse: central nervous system immunopharmacotherapy.
  AAPS J, 7, E579-E586.  
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.  
15226496 M.R.Carrera, G.F.Kaufmann, J.M.Mee, M.M.Meijler, G.F.Koob, and K.D.Janda (2004).
Treating cocaine addiction with viruses.
  Proc Natl Acad Sci U S A, 101, 10416-10421.  
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.  
12943856 M.Vellard (2003).
The enzyme as drug: application of enzymes as pharmaceuticals.
  Curr Opin Biotechnol, 14, 444-450.  
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.