PDBsum entry 1xlu

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protein ligands metals links
Hydrolase PDB id
Protein chain
524 a.a. *
NAG ×3
SO4 ×3
GOL ×4
_CL ×2
Waters ×255
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: X-ray structure of di-isopropyl-phosphoro-fluoridate (dfp) i butyrylcholinesterase after aging
Structure: Butyrylcholinesterase. Chain: a. Synonym: acylcholine acylhydrolase. Choline esterase ii. Butyrylcholine esterase. Pseudocholinesterase. Engineered: yes. Mutation: yes. Other_details: aged, ser 198 covalently bound to isp
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: baby hampster kidney cells.
2.20Å     R-factor:   0.196     R-free:   0.242
Authors: F.Nachon,O.A.Asojo,G.E.O.Borgstahl,P.Masson,O.Lockridge
Key ref:
F.Nachon et al. (2005). Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging. Biochemistry, 44, 1154-1162. PubMed id: 15667209 DOI: 10.1021/bi048238d
30-Sep-04     Release date:   01-Feb-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P06276  (CHLE_HUMAN) -  Cholinesterase
602 a.a.
524 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 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
 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  


DOI no: 10.1021/bi048238d Biochemistry 44:1154-1162 (2005)
PubMed id: 15667209  
Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging.
F.Nachon, O.A.Asojo, G.E.Borgstahl, P.Masson, O.Lockridge.
Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
21064131 M.Amitay, and A.Shurki (2011).
Hydrolysis of organophosphate compounds by mutant butyrylcholinesterase: a story of two histidines.
  Proteins, 79, 352-364.  
20395308 B.Li, I.Ricordel, L.M.Schopfer, F.Baud, B.Mégarbane, F.Nachon, P.Masson, and O.Lockridge (2010).
Detection of adduct on tyrosine 411 of albumin in humans poisoned by dichlorvos.
  Toxicol Sci, 116, 23-31.  
20809544 B.Li, I.Ricordel, L.M.Schopfer, F.Baud, B.Mégarbane, P.Masson, and O.Lockridge (2010).
Dichlorvos, chlorpyrifos oxon and Aldicarb adducts of butyrylcholinesterase, detected by mass spectrometry in human plasma following deliberate overdose.
  J Appl Toxicol, 30, 559-565.  
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.  
19715348 C.Gilley, M.MacDonald, F.Nachon, L.M.Schopfer, J.Zhang, J.R.Cashman, and O.Lockridge (2009).
Nerve agent analogues that produce authentic soman, sarin, tabun, and cyclohexyl methylphosphonate-modified human butyrylcholinesterase.
  Chem Res Toxicol, 22, 1680-1688.  
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
19452557 M.Amitay, and A.Shurki (2009).
The structure of G117H mutant of butyrylcholinesterase: nerve agents scavenger.
  Proteins, 77, 370-377.  
19271773 T.M.Epstein, U.Samanta, S.D.Kirby, D.M.Cerasoli, and B.J.Bahnson (2009).
Crystal structures of brain group-VIII phospholipase A2 in nonaged complexes with the organophosphorus nerve agents soman and sarin.
  Biochemistry, 48, 3425-3435.
PDB codes: 3dt6 3dt8 3dt9
19394314 U.Samanta, S.D.Kirby, P.Srinivasan, D.M.Cerasoli, and B.J.Bahnson (2009).
Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.
  Biochem Pharmacol, 78, 420-429.
PDB codes: 3f96 3f97 3f98 3f9c
18939839 A.J.Smith, R.Müller, M.D.Toscano, P.Kast, H.W.Hellinga, D.Hilvert, and K.N.Houk (2008).
Structural reorganization and preorganization in enzyme active sites: comparisons of experimental and theoretically ideal active site geometries in the multistep serine esterase reaction cycle.
  J Am Chem Soc, 130, 15361-15373.  
18502412 H.Grigoryan, L.M.Schopfer, C.M.Thompson, A.V.Terry, P.Masson, and O.Lockridge (2008).
Mass spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin: a potential mechanism of long term toxicity by organophosphorus agents.
  Chem Biol Interact, 175, 180-186.  
18824507 O.D.Ekici, M.Paetzel, and R.E.Dalbey (2008).
Unconventional serine proteases: variations on the catalytic Ser/His/Asp triad configuration.
  Protein Sci, 17, 2023-2037.  
18577514 O.Lockridge, W.Xue, A.Gaydess, H.Grigoryan, S.J.Ding, L.M.Schopfer, S.H.Hinrichs, and P.Masson (2008).
Pseudo-esterase activity of human albumin: slow turnover on tyrosine 411 and stable acetylation of 82 residues including 59 lysines.
  J Biol Chem, 283, 22582-22590.  
18707141 S.J.Ding, J.Carr, J.E.Carlson, L.Tong, W.Xue, Y.Li, L.M.Schopfer, B.Li, F.Nachon, O.Asojo, C.M.Thompson, S.H.Hinrichs, P.Masson, and O.Lockridge (2008).
Five tyrosines and two serines in human albumin are labeled by the organophosphorus agent FP-biotin.
  Chem Res Toxicol, 21, 1787-1794.  
17407327 C.D.Fleming, C.C.Edwards, S.D.Kirby, D.M.Maxwell, P.M.Potter, D.M.Cerasoli, and M.R.Redinbo (2007).
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
  Biochemistry, 46, 5063-5071.
PDB codes: 2hrq 2hrr
17417839 J.DeChancie, and K.N.Houk (2007).
The origins of femtomolar protein-ligand binding: hydrogen-bond cooperativity and desolvation energetics in the biotin-(strept)avidin binding site.
  J Am Chem Soc, 129, 5419-5429.  
17766382 J.Dechancie, F.R.Clemente, A.J.Smith, H.Gunaydin, Y.L.Zhao, X.Zhang, and K.N.Houk (2007).
How similar are enzyme active site geometries derived from quantum mechanical theozymes to crystal structures of enzyme-inhibitor complexes? Implications for enzyme design.
  Protein Sci, 16, 1851-1866.  
  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
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.  
15840715 D.K.Nomura, D.Leung, K.P.Chiang, G.B.Quistad, B.F.Cravatt, and J.E.Casida (2005).
A brain detoxifying enzyme for organophosphorus nerve poisons.
  Proc Natl Acad Sci U S A, 102, 6195-6200.  
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.