Issue 10, 2013

Selective inhibition of the unfolded protein response: targeting catalytic sites for Schiff base modification

Abstract

Constitutive protein misfolding in the endoplasmic reticulum (ER) can lead to cellular toxicity and disease. Consequently, the protein folding environment within the ER is highly optimised and tightly regulated by the unfolded protein response (UPR). The apparent convergence of myriad diseases upon proteostasis in the ER has triggered a broad effort to identify selective inhibitors of the UPR. In particular, the most ancient component of this cellular stress pathway, the transmembrane protein IRE1, represents an appealing target for pharmacological intervention. Several inhibitors of IRE1 have recently been reported, each containing an aldehyde moiety that forms an unusual, highly selective Schiff base with a single key lysine (K907) within the RNase domain. Here we review the progress made in chemical genetic manipulation of IRE1 and the unfolded protein response and discuss computational strategies to rationalise the selectivity of covalently active small molecules for their targets. As an exemplar, we provide additional evidence that K907 of IRE1 is buried within a particularly unusual environment that facilitates Schiff base formation. New free-energy calculations within a molecular dynamics (MD) simulation framework show that the pKa of K907 is reduced by ∼3.6 pKa units, relative to the model pKa of lysine in water. This significant pKa perturbation provides additional insights into the precise requirements for inhibition and for RNase catalysis by IRE1. Our computational method may represent a general approach for identifying potential covalent inhibitory lysine sites within buried protein cavities.

Graphical abstract: Selective inhibition of the unfolded protein response: targeting catalytic sites for Schiff base modification

Article information

Article type
Review Article
Submitted
18 Jun 2013
Accepted
18 Jul 2013
First published
19 Jul 2013
This article is Open Access
Creative Commons BY license

Mol. BioSyst., 2013,9, 2408-2416

Selective inhibition of the unfolded protein response: targeting catalytic sites for Schiff base modification

S. M. Tomasio, H. P. Harding, D. Ron, B. C. S. Cross and P. J. Bond, Mol. BioSyst., 2013, 9, 2408 DOI: 10.1039/C3MB70234K

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