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Updated: Aug 16, 2026

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107
Ramachandran Murali1, Xin Cheng, Alan Berezov
1Department of Pathology and Laboratory of Medicine and Abramson Cancer Research Center, University of Pennsylvania, 36th Hamilton Walk, Philadelphia, PA 19104, USA. murali@xray.med.upenn.edu
Abstract:
We have disabled TNF receptor (TNFR) function by inducing allosteric modulation of tryptophan-107 (W107) in the receptor. The allosteric effect operates by means of an allosteric cavity found a short distance from a previously identified loop involved in ligand binding. Occupying this cavity by small molecules leads to perturbation of distal W107 and disables functions of the TNFR, a molecule not known to undergo conformational change upon binding TNF-alpha. TNF-alpha-induced NF-kappaB and p38 kinase activities and clinical symptoms of collagen-induced arthritis in mice were all diminished. Thus, disabling receptor function by induced conformational changes of active binding surfaces represents an innovative paradigm in structure-based drug design.
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