Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107

Ramachandran Murali, Xin Cheng, Alan Berezov, Xiulian Du, Arnie Schön, Ernesto Freire, Xiaowei Xu, Youhai H. Chen, Mark I. Greene

Research output: Contribution to journalArticlepeer-review

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-α. TNF-α-induced NF-κB 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.

Original languageEnglish (US)
Pages (from-to)10970-10975
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number31
DOIs
StatePublished - Aug 2 2005

Keywords

  • Allosteric
  • Arthritis
  • Drug design
  • Inhibitor
  • Structure

ASJC Scopus subject areas

  • General

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