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

doi:10.1073/pnas.0504301102

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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 language	English (US)
Pages (from-to)	10970-10975
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	102
Issue number	31
DOIs	https://doi.org/10.1073/pnas.0504301102
State	Published - Aug 2 2005

Keywords

Allosteric
Arthritis
Drug design
Inhibitor
Structure

ASJC Scopus subject areas

General

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10.1073/pnas.0504301102

Cite this

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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.",

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AU - Cheng, Xin

AU - Berezov, Alan

AU - Du, Xiulian

AU - Schön, Arnie

AU - Freire, Ernesto

AU - Xu, Xiaowei

AU - Chen, Youhai H.

AU - Greene, Mark I.

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Y1 - 2005/8/2

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AB - 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.

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KW - Drug design

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KW - Structure

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

Abstract

Keywords

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