NMR-based exploration of the acceptor binding site of human blood group B galactosyltransferase with molecular fragments |
| |
Authors: | Christoph Rademacher Jens Landström Nora Sindhuwinata Monica M Palcic Göran Widmalm Thomas Peters |
| |
Institution: | (1) Institute of Chemistry, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany;(2) Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden;(3) Carlsberg Laboratory, Gamle Carlsberg Vej10, DK-2500 Valby, Denmark; |
| |
Abstract: | A substantial body of work has been devoted to the design and synthesis of glycosyltransferase inhibitors. A major obstacle
has always been the demanding chemistry. Therefore, only few potent and selective inhibitors are known to date. Glycosyltransferases
possess two distinct binding sites, one for the donor substrate, and one for the acceptor substrate. In many cases binding
to the donor site is well defined but data for acceptor binding is sparse. In particular, acceptor binding sites are often
shallow, and in many cases the dimensions of the binding pocket are not well defined. One approach to glycosyltransferase
inhibitors is to chemically link donor site and acceptor site ligands to generate high affinity binders. Here, we describe
a novel approach to identify acceptor site ligands from a fragment library. We have chosen human blood group B galactosyltransferase
(GTB) as a biologically important model target. The approach utilizes a combination of STD NMR, spin-lock filtered NMR experiments
and surface plasmon resonance measurements. Following this route we have identified molecular fragments from a fragment library
that bind to the acceptor site of GTB with affinities of the order of a natural acceptor substrate. Unlike natural substrates
these fragments allow for straightforward chemical modifications and, therefore will serve as scaffolds for potent GTB inhibitors.
In general, the approach described is applicable to any glycosyltransferase and may assist in the development of novel glycosyltransferase
inhibitors. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|