| Literature DB >> 16043718 |
Ramachandran Murali1, Xin Cheng, Alan Berezov, Xiulian Du, Arnie Schön, Ernesto Freire, Xiaowei Xu, Youhai H Chen, Mark I Greene.
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.Entities:
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Year: 2005 PMID： 16043718 PMCID： PMC1182441 DOI： 10.1073/pnas.0504301102
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205