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PDBsum entry 2dr0

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2dr0
Jmol
Contents
Protein chain
532 a.a. *
Ligands
NAG ×2
SIA ×3
SO4 ×6
TCH ×6
NDG
Waters ×253
* Residue conservation analysis
PDB id:
2dr0
Name: Hydrolase
Title: Crystal structure of human carboxylesterase in complex with taurocholate
Structure: Liver carboxylesterase 1. Chain: a, b, c. Fragment: residues 19-561. 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. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
3.20Å     R-factor:   0.219     R-free:   0.255
Authors: S.Bencharit,M.R.Redinbo
Key ref:
S.Bencharit et al. (2006). Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1. J Mol Biol, 363, 201-214. PubMed id: 16962139 DOI: 10.1016/j.jmb.2006.08.025
Date:
02-Jun-06     Release date:   29-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23141  (EST1_HUMAN) -  Liver carboxylesterase 1
Seq:
Struc:
 
Seq:
Struc:
567 a.a.
532 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.3.1.1.1  - 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.3.1.1.56  - 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  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2006.08.025 J Mol Biol 363:201-214 (2006)
PubMed id: 16962139  
 
 
Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1.
S.Bencharit, C.C.Edwards, C.L.Morton, E.L.Howard-Williams, P.Kuhn, P.M.Potter, M.R.Redinbo.
 
  ABSTRACT  
 
Human carboxylesterase 1 (hCE1) is a drug and endobiotic-processing serine hydrolase that exhibits relatively broad substrate specificity. It has been implicated in a variety of endogenous cholesterol metabolism pathways including the following apparently disparate reactions: cholesterol ester hydrolysis (CEH), fatty acyl Coenzyme A hydrolysis (FACoAH), acyl-Coenzyme A:cholesterol acyltransfer (ACAT), and fatty acyl ethyl ester synthesis (FAEES). The structural basis for the ability of hCE1 to perform these catalytic actions involving large substrates and products has remained unclear. Here we present four crystal structures of the hCE1 glycoprotein in complexes with the following endogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and taurocholate. While the active site of hCE1 was known to be promiscuous and capable of interacting with a variety of chemically distinct ligands, these structures reveal that the enzyme contains two additional ligand-binding sites and that each site also exhibits relatively non-specific ligand-binding properties. Using this multisite promiscuity, hCE1 appears structurally capable of assembling several catalytic events depending, apparently, on the physiological state of the cellular environment. These results expand our understanding of enzyme promiscuity and indicate that, in the case of hCE1, multiple non-specific sites are employed to perform distinct catalytic actions.
 
  Selected figure(s)  
 
Figure 1.
Figure 4.
 
  The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2006, 363, 201-214) copyright 2006.  
  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.  
20623318 G.Vistoli, A.Pedretti, A.Mazzolari, and B.Testa (2010).
Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.
  J Comput Aided Mol Des, 24, 771-787.  
19761868 J.A.Crow, K.L.Herring, S.Xie, A.Borazjani, P.M.Potter, and M.K.Ross (2010).
Inhibition of carboxylesterase activity of THP1 monocytes/macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids.
  Biochim Biophys Acta, 1801, 31-41.  
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.  
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.  
19363507 G.A.Mitchell (2009).
Genetics, physiology and perinatal influences in childhood obesity: view from the Chair.
  Int J Obes (Lond), 33, S41-S47.  
19332024 M.Jernås, B.Olsson, P.Arner, P.Jacobson, L.Sjöström, A.Walley, P.Froguel, P.G.McTernan, J.Hoffstedt, and L.M.Carlsson (2009).
Regulation of carboxylesterase 1 (CES1) in human adipose tissue.
  Biochem Biophys Res Commun, 383, 63-67.  
  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.  
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.  
18762277 J.A.Crow, B.L.Middleton, A.Borazjani, M.J.Hatfield, P.M.Potter, and M.K.Ross (2008).
Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages.
  Biochim Biophys Acta, 1781, 643-654.  
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.  
18163883 T.M.Streit, A.Borazjani, S.E.Lentz, M.Wierdl, P.M.Potter, S.R.Gwaltney, and M.K.Ross (2008).
Evaluation of the 'side door' in carboxylesterase-mediated catalysis and inhibition.
  Biol Chem, 389, 149-162.  
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
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.