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PDBsum entry 1h23

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Hydrolase PDB id
1h23
Jmol
Contents
Protein chain
528 a.a. *
Ligands
E12
NAG ×2
Waters ×269
* Residue conservation analysis
PDB id:
1h23
Name: Hydrolase
Title: Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (s,s)-(-)-bis(12)-hupyridone at 2.15a resolution
Structure: Acetylcholinesterase. Chain: a. Synonym: ache. Other_details: inter-monomer disulfide bridge
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque. Other_details: synthetic bivalent hupa-like dimer, (s, s)-(-)-bis(12)-hupyridone ((s, s)-(-)-n, n'-di-5'- -[5', 6', 7', 8'-tetrahydro-2'(1'h)-quinolinonyl] 1,
Resolution:
2.15Å     R-factor:   0.189     R-free:   0.214
Authors: D.M.Wong,H.M.Greenblatt,P.R.Carlier,Y.F.Han,Y.P.Pang, I.Silman,J.L.Sussman
Key ref: D.M.Wong et al. (2003). Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity. J Am Chem Soc, 125, 363-373. PubMed id: 12517147 DOI: 10.1021/ja021111w
Date:
30-Jul-02     Release date:   23-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
586 a.a.
528 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!
  Cellular component     synapse   5 terms 
  Biological process     neurotransmitter catabolic process   2 terms 
  Biochemical function     carboxylic ester hydrolase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ja021111w J Am Chem Soc 125:363-373 (2003)
PubMed id: 12517147  
 
 
Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity.
D.M.Wong, H.M.Greenblatt, H.Dvir, P.R.Carlier, Y.F.Han, Y.P.Pang, I.Silman, J.L.Sussman.
 
  ABSTRACT  
 
Acetylcholinesterase (AChE) inhibitors improve the cognitive abilities of Alzheimer patients. (-)-Huperzine A [(-)-HupA], an alkaloid isolated from the club moss, Huperzia serrata, is one such inhibitor, but the search for more potent and selective drugs continues. Recently, alkylene-linked dimers of 5-amino-5,6,7,8-tetrahydroquinolinone (hupyridone, 1a), a fragment of HupA, were shown to serve as more potent inhibitors of AChE than (-)-HupA and monomeric 1a. We soaked two such dimers, (S,S)-(-)-bis(10)-hupyridone [(S,S)-(-)-2a] and (S,S)-(-)-bis(12)-hupyridone [(S,S)-(-)-2b] containing, respectively, 10 and 12 methylenes in the spacer, into trigonal TcAChE crystals, and solved the X-ray structures of the resulting complexes using the difference Fourier technique, both to 2.15 A resolution. The structures revealed one HupA-like 1a unit bound to the "anionic" subsite of the active-site, near the bottom of the active-site gorge, adjacent to Trp84, as seen for the TcAChE/(-)-HupA complex, and the second 1a unit near Trp279 in the "peripheral" anionic site at the top of the gorge, both bivalent molecules thus spanning the active-site gorge. The results confirm that the increased affinity of the dimeric HupA analogues for AChE is conferred by binding to the two "anionic" sites of the enzyme. Inhibition data show that (-)-2a binds to TcAChE approximately 6-7- and > 170-fold more tightly than (-)-2b and (-)-HupA, respectively. In contrast, previous data for rat AChE show that (-)-2b binds approximately 3- and approximately 2-fold more tightly than (-)-2a and (-)-HupA, respectively. Structural comparison of TcAChE with rat AChE, as represented by the closely related mouse AChE structure (1maa.pdb), reveals a narrower gorge for rat AChE, a perpendicular alignment of the Tyr337 ring to the gorge axis, and its conformational rigidity, as a result of hydrogen bonding between its hydroxyl group and that of Tyr341, relative to TcAChE Phe330. These structural differences in the active-site gorge explain the switch in inhibitory potency of (-)-2a and 2b and the larger dimer/(-)-HupA potency ratios observed for TcAChE relative to rat AChE. The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21271607 H.Yu, Y.Q.Hu, F.C.Ip, Z.Zuo, Y.F.Han, and N.Y.Ip (2011).
Intestinal transport of bis(12)-hupyridone in Caco-2 cells and its improved permeability by the surfactant Brij-35.
  Biopharm Drug Dispos, 32, 140-150.  
21216144 Z.F.Al-Rashid, and R.P.Hsung (2011).
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
  Bioorg Med Chem Lett, 21, 2687-2691.  
20922228 Y.Zhang, M.Angelin, R.Larsson, A.Albers, A.Simons, and O.Ramström (2010).
Tandem driven dynamic self-inhibition of acetylcholinesterase.
  Chem Commun (Camb), 46, 8457-8459.  
18273558 T.A.Pham, and A.N.Jain (2008).
Customizing scoring functions for docking.
  J Comput Aided Mol Des, 22, 269-286.  
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.  
18033585 J.Stöckigt, and S.Panjikar (2007).
Structural biology in plant natural product biosynthesis--architecture of enzymes from monoterpenoid indole and tropane alkaloid biosynthesis.
  Nat Prod Rep, 24, 1382-1400.  
17075950 B.D.Charette, R.G.Macdonald, S.Wetzel, D.B.Berkowitz, and H.Waldmann (2006).
Protein structure similarity clustering: dynamic treatment of PDB structures facilitates clustering.
  Angew Chem Int Ed Engl, 45, 7766-7770.  
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.  
16404617 Q.Xie, Y.Tang, W.Li, X.H.Wang, and Z.B.Qiu (2006).
Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.
  J Mol Model, 12, 390-397.  
16263176 T.S.Anekonda, and P.H.Reddy (2005).
Can herbs provide a new generation of drugs for treating Alzheimer's disease?
  Brain Res Brain Res Rev, 50, 361-376.  
16113998 Y.Umezawa, and M.Nishio (2005).
CH/pi hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase.
  Biopolymers, 79, 248-258.  
14519922 H.Takayama, K.Katakawa, M.Kitajima, K.Yamaguchi, and N.Aimi (2003).
Ten new Lycopodium alkaloids having the lycopodane skeleton isolated from Lycopodium serratum Thunb.
  Chem Pharm Bull (Tokyo), 51, 1163-1169.  
12837382 Y.P.Pang, T.M.Kollmeyer, F.Hong, J.C.Lee, P.I.Hammond, S.P.Haugabouk, and S.Brimijoin (2003).
Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
  Chem Biol, 10, 491-502.
PDB codes: 1jga 1jgb 1puv 1puw
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.