PDBsum entry: 1p0p

Hydrolase

PDB id: 1p0p

Contents

Protein chain

522 a.a. *

Ligands

NAG-NAG-FUC ×2

NAG ×3

SO4

VXA

BCH

GOL

Metals

_CL ×2

Waters ×337

* Residue conservation analysis

PDB id:

1p0p

Name:

Hydrolase

Title:

Crystal structure of soman-aged human butyryl cholinesterase complex with the substrate analog butyrylthiocholine

Structure:

Cholinesterase. Chain: a. Synonym: acylcholine acylhydrolase, choline esterase ii, butyrylcholine esterase, pseudocholinesterase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bche or che1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: ovary cells

Resolution:

2.30Å R-factor: 0.199 R-free: 0.242

Authors:

Y.Nicolet,O.Lockridge,P.Masson,J.C.Fontecilla-Camps,F.Nachon

Key ref:

Y.Nicolet et al. (2003). Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J Biol Chem, 278, 41141-41147. PubMed id: 12869558 DOI: 10.1074/jbc.M210241200

Date:

10-Apr-03 Release date: 05-Aug-03

Protein chain

P06276  (CHLE_HUMAN) -  Cholinesterase

Seq: 602 a.a.

Struc: 522 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.1.8 - Cholinesterase.
• Reaction: An acylcholine + H₂O = choline + a carboxylate

acylcholine + H(2)O = choline (Bound ligand (Het Group name = BCH) matches with 46.15% similarity) + carboxylate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (7 terms)
• Biological process: metabolic process (11 terms)
• Biochemical function: catalytic activity (8 terms)

reference

DOI no: 10.1074/jbc.M210241200

J Biol Chem 278:41141-41147 (2003)

PubMed id: 12869558

Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products.

Y.Nicolet, O.Lockridge, P.Masson, J.C.Fontecilla-Camps, F.Nachon.

ABSTRACT

Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser(198) has been modeled as bound butyrate.

Selected figure(s)

Figure 3.
FIG. 3. Difference Fourier electron density maps for bonded and non-bonded butyrate. a, tetrahedral model. Despite the restrains applied the C-O distance is 1.47 Å, and there is a residual negative electron density peak at -5.7 between these two atoms. The average B-factor for the buryrate moiety is 44 Å2 and that of the tetrahedral C atom is 51.1 Å2 (comparable values for the model with a 2.16-Å-long C-O bond depicted in Fig. 2 are 41.7 and 41.4 Å, respectively). b, non-bonded butyrate model. The C-O distance refines to 2.6 Å, and there is a negative peak at -3.7 below the carboxylate carbon atom. The average B-factor for the buryrate moiety is 41.7 Å2 and that of the carboxylate carbon atom is 45.8 Å2.

Figure 5.
FIG. 5. a, stereo view of the active site after soaking one of the original crystals in a 100 mM choline solution. The orientation is the same as in Fig. 2. b, stereo view of the same structure rotated by 90° around an horizontal axis relative to a. The catalytic serine side chain adopts two different conformations: one where the O interacts with His438 and the other where it replaces a water molecule that interacted with the main chain nitrogen of Ala^199, in the oxyanion hole. c, stereo view of the active site of the soman-aged butyrylthiocholine-BChE complex oriented as in Fig. 1. The 2.3-Å resolution difference Fourier omit map is depicted in green. The covalently bound methylphosphonyl moiety occupies the same position as in soman-aged TcAChE (35). As expected, the quaternary ammonium group of butyrylthiocholine is located in the -cation site, but the substrate adopts a non-productive orientation (see "Results"). The omit Fourier electron density maps show that choline and butyrylthiocholine occupy very similar positions and that the alcohol function of the former and the carbonyl oxygen of the latter establish hydrogen bonds with equivalent water molecules. In all three panels the omit maps are depicted in green and are contoured at a 3 level.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 41141-41147) copyright 2003.

Figures were selected by an automated process.