Open AccessDisabling TNF receptor signaling by induced conformational perturbation of tryptophan-107
Author(s) -
Ramachandran Murali,
Xin Cheng,
Alan Berezov,
Xiulian Du,
Arnie Schön,
Ernesto Freire,
Xiaowei Xu,
Youhai H. Chen,
Mark I. Greene
Publication year - 2005
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0504301102
Subject(s) - allosteric regulation , conformational change , receptor , allosteric enzyme , tryptophan , chemistry , allosteric modulator , small molecule , binding site , biophysics , microbiology and biotechnology , stereochemistry , biochemistry , biology , amino acid
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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