PDBsum entry 1yaj

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Hydrolase PDB id
Jmol PyMol
Protein chain
(+ 6 more) 532 a.a. *
NAG ×12
SIA ×12
SO4 ×24
BEZ ×24
Waters ×474
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of human liver carboxylesterase in complex benzil
Structure: Ces1 protein. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Trimer (from PQS)
3.20Å     R-factor:   0.207     R-free:   0.287
Authors: C.D.Fleming,S.Bencharit,C.C.Edwards,J.L.Hyatt,C.M.Morton,E.L Williams,P.M.Potter,M.R.Redinbo
Key ref:
C.D.Fleming et al. (2005). Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil. J Mol Biol, 352, 165-177. PubMed id: 16081098 DOI: 10.1016/j.jmb.2005.07.016
17-Dec-04     Release date:   02-Aug-05    
Go to PROCHECK summary

Protein chains
-  (POLG_HAVHM) - 
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   3 terms 
  Biological process     metabolic process   7 terms 
  Biochemical function     carboxylic ester hydrolase activity     4 terms  


DOI no: 10.1016/j.jmb.2005.07.016 J Mol Biol 352:165-177 (2005)
PubMed id: 16081098  
Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil.
C.D.Fleming, S.Bencharit, C.C.Edwards, J.L.Hyatt, L.Tsurkan, F.Bai, C.Fraga, C.L.Morton, E.L.Howard-Williams, P.M.Potter, M.R.Redinbo.
Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.
  Selected figure(s)  
Figure 4.
Figure 4. Binding of tamoxifen by hCE1. (a) Stereo view of simulated annealing omit map of tamoxifen (gold) bound to the active site of hCE1. Maps are at 3.2 Å resolution and contoured to 3.0 s (blue) and 2.0 s (magenta). (b) Tamoxifen bound within the active site gorge. The molecular surface of tamoxifen (green) and the surface of the hCE1 active site (gold) indicate that the drug fits in a complementary manner. Amino acid residues making hydrophobic contacts with tamoxifen are boxed in black. (c) Relationship of the active site to the Z-site in the hCE1-tamoxifen complex. The secondary structure is labeled and tamoxifen is shown in gold.
Figure 5.
Figure 5. hCE1 inhibition by benzil. (a) Proposed mechanism of benzil inhibition and processing by hCE1. Non covalent products NCP1 (benzaldehyde, in purple) or NCP2, (benzoic acid, in blue) are found in nine out of 12 active sites, with the covalent product (COV) found in three of 12 active sites, depicted in red. (b) Covalent modification of the catalytic serine residue by benzil. The catalytic triad is labeled in grey with the oxyanion hole in blue. (c) NCP2 bound to the active site of hCE1. The catalytic water molecule is represented as a red sphere and amino acid residues are labeled as in (b). (d) Stereo views of the simulated annealing omit maps at 3.2 Å resolution of the active site COV and NCP2 complexed with hCE1, contoured to 2.0 s (magenta) and 4.0 s (blue).
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 352, 165-177) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20966115 G.Li, J.E.Janecka, and W.J.Murphy (2011).
Accelerated evolution of CES7, a gene encoding a novel major urinary protein in the cat family.
  Mol Biol Evol, 28, 911-920.  
20676708 J.Rayo, L.Muñoz, G.Rosell, B.D.Hammock, A.Guerrero, F.J.Luque, and R.Pouplana (2010).
Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study.
  J Mol Model, 16, 1753-1764.  
20532832 P.Li, C.L.Zhu, X.X.Zhang, L.Gan, H.Z.Yu, and Y.Gan (2010).
Reversible inhibitory effects of saturated and unsaturated alkyl esters on the carboxylesterases activity in rat intestine.
  Lipids, 45, 603-612.  
20422440 R.S.Holmes, L.A.Cox, and J.L.VandeBerg (2010).
Mammalian carboxylesterase 3: comparative genomics and proteomics.
  Genetica, 138, 695-708.  
20931200 R.S.Holmes, M.W.Wright, S.J.Laulederkind, L.A.Cox, M.Hosokawa, T.Imai, S.Ishibashi, R.Lehner, M.Miyazaki, E.J.Perkins, P.M.Potter, M.R.Redinbo, J.Robert, T.Satoh, T.Yamashita, B.Yan, T.Yokoi, R.Zechner, and L.J.Maltais (2010).
Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins.
  Mamm Genome, 21, 427-441.  
20430828 X.Liu, S.Ouyang, B.Yu, Y.Liu, K.Huang, J.Gong, S.Zheng, Z.Li, H.Li, and H.Jiang (2010).
PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach.
  Nucleic Acids Res, 38, W609-W614.  
19937843 G.Vistoli, A.Pedretti, A.Mazzolari, C.Bolchi, and B.Testa (2009).
Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study.
  Chem Biodivers, 6, 2092-2100.  
19187434 R.S.Holmes, J.P.Glenn, J.L.VandeBerg, and L.A.Cox (2009).
Baboon carboxylesterases 1 and 2: sequences, structures and phylogenetic relationships with human and other primate carboxylesterases.
  J Med Primatol, 38, 27-38.  
20161041 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
A new class of mammalian carboxylesterase CES6.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 209-217.  
20161341 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
Bovine Carboxylesterases: Evidence for Two CES1 and Five Families of CES Genes on Chromosome 18.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 11-20.  
20403742 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
Horse carboxylesterases: evidence for six CES1 and four families of CES genes on chromosome 3.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 54-65.  
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.  
18023188 C.E.Wheelock, K.Nishi, A.Ying, P.D.Jones, M.E.Colvin, M.M.Olmstead, and B.D.Hammock (2008).
Influence of sulfur oxidation state and steric bulk upon trifluoromethyl ketone (TFK) binding kinetics to carboxylesterases and fatty acid amide hydrolase (FAAH).
  Bioorg Med Chem, 16, 2114-2130.  
18485328 H.J.Zhu, K.S.Patrick, H.J.Yuan, J.S.Wang, J.L.Donovan, C.L.DeVane, R.Malcolm, J.A.Johnson, G.L.Youngblood, D.H.Sweet, T.Y.Langaee, and J.S.Markowitz (2008).
Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis.
  Am J Hum Genet, 82, 1241-1248.  
18273909 O.T.Oboh, and N.S.Lamango (2008).
Liver prenylated methylated protein methyl esterase is the same enzyme as Sus scrofa carboxylesterase.
  J Biochem Mol Toxicol, 22, 51-62.  
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.  
19727319 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2008).
Mammalian carboxylesterase 5: comparative biochemistry and genomics.
  Comp Biochem Physiol Part D Genomics Proteomics, 3, 195-204.  
18383336 S.Takahashi, M.Katoh, T.Saitoh, M.Nakajima, and T.Yokoi (2008).
Allosteric kinetics of human carboxylesterase 1: species differences and interindividual variability.
  J Pharm Sci, 97, 5434-5445.  
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
17239398 P.Liu, H.E.Ewis, P.C.Tai, C.D.Lu, and I.T.Weber (2007).
Crystal structure of the Geobacillus stearothermophilus carboxylesterase Est55 and its activation of prodrug CPT-11.
  J Mol Biol, 367, 212-223.
PDB codes: 2ogs 2ogt
17167034 R.M.Wadkins, J.L.Hyatt, C.C.Edwards, L.Tsurkan, M.R.Redinbo, C.E.Wheelock, P.D.Jones, B.D.Hammock, and P.M.Potter (2007).
Analysis of mammalian carboxylesterase inhibition by trifluoromethylketone-containing compounds.
  Mol Pharmacol, 71, 713-723.  
16962139 S.Bencharit, C.C.Edwards, C.L.Morton, E.L.Howard-Williams, P.Kuhn, P.M.Potter, and M.R.Redinbo (2006).
Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1.
  J Mol Biol, 363, 201-214.
PDB codes: 2dqy 2dqz 2dr0 2h7c
16858120 T.Imai (2006).
Human carboxylesterase isozymes: catalytic properties and rational drug design.
  Drug Metab Pharmacokinet, 21, 173-185.  
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.