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PDBsum entry 1q83

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
1q83
Jmol
Contents
Protein chains
536 a.a. *
Ligands
NAG-FUL
NAG ×2
P6G
TZ5 ×2
Waters ×273
* Residue conservation analysis
PDB id:
1q83
Name: Hydrolase
Title: Crystal structure of the mouse acetylcholinesterase-tz2pa6 s
Structure: Acetylcholinesterase. Chain: a, b. Synonym: ache. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: ache. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek 293. Other_details: lambda-zap, lambda-fix cdna
Resolution:
2.65Å     R-factor:   0.183     R-free:   0.221
Authors: Y.Bourne,H.C.Kolb,Z.Radic,K.B.Sharpless,P.Taylor,P.Marchot
Key ref:
Y.Bourne et al. (2004). Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation. Proc Natl Acad Sci U S A, 101, 1449-1454. PubMed id: 14757816 DOI: 10.1073/pnas.0308206100
Date:
20-Aug-03     Release date:   10-Feb-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
536 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.7  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Acetylcholine
Bound ligand (Het Group name = NAG)
matches with 41.18% similarity
+ H(2)O
= choline
+ acetate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     cholinesterase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0308206100 Proc Natl Acad Sci U S A 101:1449-1454 (2004)
PubMed id: 14757816  
 
 
Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation.
Y.Bourne, H.C.Kolb, Z.Radić, K.B.Sharpless, P.Taylor, P.Marchot.
 
  ABSTRACT  
 
The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Overall fold and structural quality of the TZ2PA6-mAChE complexes. (A) Overall view of the mAChE molecule (cyan ribbon) showing the syn1 isomer (orange bonds; transparent molecular surface) bound within the enzyme active-site gorge; the long loop Cys-69-Cys-96 is displayed in yellow. (B and C) Determined structures of the bound anti1 and syn1 isomers (yellow and orange bonds, respectively; blue nitrogens; numbered triazole atoms; same orientation as in Scheme 1), with the respective 2.45- and 2.65-Å resolution final 2F[o]-F[c] electron density maps contoured at 1 (cyan).
Figure 3.
Fig. 3. Distinctive topographies of the PAS regions in the anti1 and syn1 complexes. Views of the PAS region of mAChE bound to the phenanthridinium moiety present in the anti1 (A) and syn1 (B) isomers (colored as in Figs. 1 and 2). The mAChE molecular surfaces buried at the complex interfaces are shown in yellow, with the Tyr-72 and Trp-286 side chains highlighted in green and magenta, respectively. The mAChE surface areas (Connolly's surfaces) buried to a 1.6-Å radius probe at the anti1 and syn1 complex interfaces by the phenylphenanthridinium and linker first carbon are 256 and 313 Å2 (the double-face burying of the syn1 phenanthridinium being counterbalanced by the deeper burying of the anti1 phenyl). The gorge mouth openings (Richards' surface) for the anti1 and syn1 complexes are 14 and 29 Å2, respectively.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21397508 A.Shi, L.Huang, C.Lu, F.He, and X.Li (2011).
Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors.
  Bioorg Med Chem, 19, 2298-2305.  
21226087 C.M.So, C.P.Lau, and F.Y.Kwong (2011).
Palladium-catalyzed direct arylation of heteroarenes with aryl mesylates.
  Chemistry, 17, 761-765.  
20444867 D.Douguet (2010).
e-LEA3D: a computational-aided drug design web server.
  Nucleic Acids Res, 38, W615-W621.  
20309485 S.K.Mamidyala, and M.G.Finn (2010).
In situ click chemistry: probing the binding landscapes of biological molecules.
  Chem Soc Rev, 39, 1252-1261.  
20154467 T.Hirose, T.Sunazuka, and S.Omura (2010).
Recent development of two chitinase inhibitors, Argifin and Argadin, produced by soil microorganisms.
  Proc Jpn Acad Ser B Phys Biol Sci, 86, 85.  
20309488 X.Hu, and R.Manetsch (2010).
Kinetic target-guided synthesis.
  Chem Soc Rev, 39, 1316-1324.  
19122913 B.Liu, and D.Cui (2009).
Rare-earth metal complexes stabilized by amino-phosphine ligand. Reaction with mesityl azide and catalysis of the cycloaddition of organic azides and aromatic alkynes.
  Dalton Trans, (), 550-556.  
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
19679363 M.F.Schmidt, and J.Rademann (2009).
Dynamic template-assisted strategies in fragment-based drug discovery.
  Trends Biotechnol, 27, 512-521.  
19329983 T.Hirose, T.Sunazuka, A.Sugawara, A.Endo, K.Iguchi, T.Yamamoto, H.Ui, K.Shiomi, T.Watanabe, K.B.Sharpless, and S.Omura (2009).
Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry.
  J Antibiot (Tokyo), 62, 277-282.  
19658129 Y.Wang, F.Li, Y.Han, F.Wang, and H.Jiang (2009).
Folding and aggregation of cationic oligo(aryl-triazole)s in aqueous solution.
  Chemistry, 15, 9424-9433.  
18769671 D.Toiber, A.Berson, D.Greenberg, N.Melamed-Book, S.Diamant, and H.Soreq (2008).
N-acetylcholinesterase-induced apoptosis in Alzheimer's disease.
  PLoS ONE, 3, e3108.  
17763363 G.C.Tron, T.Pirali, R.A.Billington, P.L.Canonico, G.Sorba, and A.A.Genazzani (2008).
Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes.
  Med Res Rev, 28, 278-308.  
18633524 H.Yanai, S.Obara, and T.Taguchi (2008).
An efficient synthesis of triazolo-carbohydrate mimetics and their conformational analysis.
  Org Biomol Chem, 6, 2679-2685.  
18452905 J.M.Bui, and J.Andrew McCammon (2008).
Intrinsic conformational flexibility of acetylcholinesterase.
  Chem Biol Interact, 175, 303-304.  
18599028 M.C.Dinamarca, M.Arrázola, E.Toledo, W.F.Cerpa, J.Hancke, and N.C.Inestrosa (2008).
Release of acetylcholinesterase (AChE) from beta-amyloid plaques assemblies improves the spatial memory impairments in APP-transgenic mice.
  Chem Biol Interact, 175, 142-149.  
  18941482 M.Martinelli, T.Milcent, S.Ongeri, and B.Crousse (2008).
Synthesis of new triazole-based trifluoromethyl scaffolds.
  Beilstein J Org Chem, 4, 19.  
18205831 N.C.Inestrosa, M.C.Dinamarca, and A.Alvarez (2008).
Amyloid-cholinesterase interactions. Implications for Alzheimer's disease.
  FEBS J, 275, 625-632.  
18359854 Y.Xu, J.P.Colletier, H.Jiang, I.Silman, J.L.Sussman, and M.Weik (2008).
Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design.
  Protein Sci, 17, 601-605.  
18502801 Y.Xu, J.P.Colletier, M.Weik, H.Jiang, J.Moult, I.Silman, and J.L.Sussman (2008).
Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics.
  Biophys J, 95, 2500-2511.  
18555981 Z.Radić, R.Manetsch, D.Fournier, K.B.Sharpless, and P.Taylor (2008).
Probing gorge dimensions of cholinesterases by freeze-frame click chemistry.
  Chem Biol Interact, 175, 161-165.  
17913689 P.Taylor, E.Reiner, Z.Kovarik, and Z.Radić (2007).
Application of recombinant DNA methods for production of cholinesterases as organophosphate antidotes and detectors.
  Arh Hig Rada Toksikol, 58, 339-345.  
17340013 V.D.Bock, D.Speijer, H.Hiemstra, and J.H.van Maarseveen (2007).
1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics.
  Org Biomol Chem, 5, 971-975.  
17084612 D.A.Erlanson (2006).
Fragment-based lead discovery: a chemical update.
  Curr Opin Biotechnol, 17, 643-652.  
16342323 D.Rochu, C.Cléry-Barraud, F.Renault, A.Chevalier, C.Bon, and P.Masson (2006).
Capillary electrophoresis versus differential scanning calorimetry for the analysis of free enzyme versus enzyme-ligand complexes: in the search of the ligand-free status of cholinesterases.
  Electrophoresis, 27, 442-451.  
16791318 G.Pastorin, S.Marchesan, J.Hoebeke, T.Da Ros, L.Ehret-Sabatier, J.P.Briand, M.Prato, and A.Bianco (2006).
Design and activity of cationic fullerene derivatives as inhibitors of acetylcholinesterase.
  Org Biomol Chem, 4, 2556-2562.  
15934050 A.Brik, J.Alexandratos, Y.C.Lin, J.H.Elder, A.J.Olson, A.Wlodawer, D.S.Goodsell, and C.H.Wong (2005).
1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors.
  Chembiochem, 6, 1167-1169.
PDB codes: 1zp8 1zpa
16100733 S.Bräse, C.Gil, K.Knepper, and V.Zimmermann (2005).
Organic azides: an exploding diversity of a unique class of compounds.
  Angew Chem Int Ed Engl, 44, 5188-5240.  
15791209 Y.Bourne, T.T.Talley, S.B.Hansen, P.Taylor, and P.Marchot (2005).
Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.
  EMBO J, 24, 1512-1522.
PDB code: 1yi5
15286733 D.C.Rees, M.Congreve, C.W.Murray, and R.Carr (2004).
Fragment-based lead discovery.
  Nat Rev Drug Discov, 3, 660-672.  
15599912 V.P.Mocharla, B.Colasson, L.V.Lee, S.Röper, K.B.Sharpless, C.H.Wong, and H.C.Kolb (2004).
In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II.
  Angew Chem Int Ed Engl, 44, 116-120.  
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.