1ACL

QUATERNARY LIGAND BINDING TO AROMATIC RESIDUES IN THE ACTIVE-SITE GORGE OF ACETYLCHOLINESTERASE

Summary for 1ACL

• Entry DOI: 10.2210/pdb1acl/pdb
• Descriptor: ACETYLCHOLINESTERASE, DECAMETHONIUM ION (3 entities in total)
• Functional Keywords: hydrolase(carboxylic esterase)
• Biological source: Torpedo californica (Pacific electric ray)
• Cellular location: Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058
• Total number of polymer chains: 1
• Total formula weight: 61051.00

Authors

Sussman, J.L.,Harel, M.,Silman, I. (deposition date: 1993-08-18, release date: 1994-08-31, Last modification date: 2024-01-17)

Primary citation

Harel, M.,Schalk, I.,Ehret-Sabatier, L.,Bouet, F.,Goeldner, M.,Hirth, C.,Axelsen, P.H.,Silman, I.,Sussman, J.L.
Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.
Proc.Natl.Acad.Sci.USA, 90:9031-9035, 1993

PubMed Abstract: Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) for quaternary ligands were investigated by x-ray crystallography and photoaffinity labeling. Crystal structures of complexes with ligands were determined at 2.8-A resolution. In a complex with edrophonium, and quaternary nitrogen of the ligand interacts with the indole of Trp-84, and its m-hydroxyl displays bifurcated hydrogen bonding to two members of the catalytic triad, Ser-200 and His-440. In a complex with tacrine, the acridine is stacked against the indole of Trp-84. The bisquaternary ligand decamethonium is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of Trp-84 and the other to that of Trp-279, near the top of the gorge. The only major conformational difference between the three complexes is in the orientation of the phenyl ring of Phe-330. In the decamethonium complex it lies parallel to the surface of the gorge; in the other two complexes it is positioned to make contact with the bound ligand. This close interaction was confirmed by photoaffinity labelling by the photosensitive probe 3H-labeled p-(N,N-dimethylamino)benzenediazonium fluoroborate, which labeled, predominantly, Phe-330 within the active site. Labeling of Trp-279 was also observed. One mole of label is incorporated per mole of AcChoEase inactivated, indicating that labeling of Trp-279 and that of Phe-330 are mutually exclusive. The structural and chemical data, together, show the important role of aromatic groups as binding sites for quaternary ligands, and they provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site and Trp-279 to the "peripheral" anionic site.

PubMed: 8415649
DOI: 10.1073/pnas.90.19.9031

Experimental method

X-RAY DIFFRACTION (2.8 Å)