PDBsum entry 1w4l

Hydrolase

PDB id: 1w4l

Contents

Protein chain

529 a.a.

Ligands

NAG-NAG

NAG ×2

GL8

Waters ×309

References listed in PDB file

Key reference

• Title: The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-Site gorge: implications for structure-Based drug design.
• Authors: H.M.Greenblatt, C.Guillou, D.Guénard, A.Argaman, S.Botti, B.Badet, C.Thal, I.Silman, J.L.Sussman.
• Ref.: J Am Chem Soc, 2004, 126, 15405-15411. [DOI no: 10.1021/ja0466154]
• PubMed id: 15563167

Abstract

Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure.

Secondary reference #1

• Title: Potent acetylcholinesterase inhibitors: design, Synthesis, And structure-Activity relationships of bis-Interacting ligands in the galanthamine series.
• Authors: A.Mary, D.Z.Renko, C.Guillou, C.Thal.
• Ref.: Bioorg Med Chem Lett, 1998, 6, 1835-1850. [DOI no: 10.1016/S0968-0896(98)00133-3]
• PubMed id: 9839013