PDBsum entry 2hrq

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
Protein chain
(+ 0 more) 532 a.a. *
NAG ×6
SIA ×6
SUC ×6
SO4 ×12
GD7 ×6
Waters ×1115
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of human liver carboxylesterase 1 (hce1) i complex with the nerve agent soman (gd)
Structure: Liver carboxylesterase 1. Chain: a, b, c, d, e, f. Synonym: acyl coenzyme a:cholesterol acyltransferase, acat, monocyte/macrophage serine esterase, hmse, serine esterase carboxylesterase hbr1, triacylglycerol hydrolase, tgh, egas engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ces1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
2.70Å     R-factor:   0.170     R-free:   0.225
Authors: C.D.Fleming,M.R.Redinbo
Key ref: C.D.Fleming et al. (2007). Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun. Biochemistry, 46, 5063-5071. PubMed id: 17407327
20-Jul-06     Release date:   01-May-07    
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Protein chains
Pfam   ArchSchema ?
P23141  (EST1_HUMAN) -  Liver carboxylesterase 1
567 a.a.
532 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Carboxylesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A carboxylic ester + H2O = an alcohol + a carboxylate
carboxylic ester
+ H(2)O
= alcohol
+ carboxylate
   Enzyme class 3: E.C.  - Methylumbelliferyl-acetate deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 4-methylumbelliferyl acetate + H2O = 4-methylumbelliferone + acetate
4-methylumbelliferyl acetate
+ H(2)O
= 4-methylumbelliferone
+ acetate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     endoplasmic reticulum   2 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     carboxylic ester hydrolase activity     3 terms  


Biochemistry 46:5063-5071 (2007)
PubMed id: 17407327  
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
C.D.Fleming, C.C.Edwards, S.D.Kirby, D.M.Maxwell, P.M.Potter, D.M.Cerasoli, M.R.Redinbo.
The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21445272 A.C.Hemmert, T.C.Otto, R.A.Chica, M.Wierdl, J.S.Edwards, S.L.Lewis, C.C.Edwards, L.Tsurkan, C.L.Cadieux, S.A.Kasten, J.R.Cashman, S.L.Mayo, P.M.Potter, D.M.Cerasoli, and M.R.Redinbo (2011).
Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.
  PLoS One, 6, e17441.  
20051531 A.C.Hemmert, T.C.Otto, M.Wierdl, C.C.Edwards, C.D.Fleming, M.MacDonald, J.R.Cashman, P.M.Potter, D.M.Cerasoli, and M.R.Redinbo (2010).
Human carboxylesterase 1 stereoselectively binds the nerve agent cyclosarin and spontaneously hydrolyzes the nerve agent sarin.
  Mol Pharmacol, 77, 508-516.
PDB code: 3k9b
20004171 P.Masson, and O.Lockridge (2010).
Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior.
  Arch Biochem Biophys, 494, 107-120.  
19539807 H.Grigoryan, B.Li, E.K.Anderson, W.Xue, F.Nachon, O.Lockridge, and L.M.Schopfer (2009).
Covalent binding of the organophosphorus agent FP-biotin to tyrosine in eight proteins that have no active site serine.
  Chem Biol Interact, 180, 492-498.  
  20664805 N.S.Lamango, R.Duverna, W.Zhang, and S.Y.Ablordeppey (2009).
Porcine Liver Carboxylesterase Requires Polyisoprenylation for High Affinity Binding to Cysteinyl Substrates.
  Open Enzym Inhib J, 2, 12-27.  
19062296 T.Harada, Y.Nakagawa, R.M.Wadkins, P.M.Potter, and C.E.Wheelock (2009).
Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis.
  Bioorg Med Chem, 17, 149-164.  
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
18550039 D.A.Jett (2008).
Cholinesterase research at the National Institutes of Health, USA.
  Chem Biol Interact, 175, 22-25.  
18289373 R.S.Holmes, J.Chan, L.A.Cox, W.J.Murphy, and J.L.VandeBerg (2008).
Opossum carboxylesterases: sequences, phylogeny and evidence for CES gene duplication events predating the marsupial-eutherian common ancestor.
  BMC Evol Biol, 8, 54.  
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 code is shown on the right.