Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107.
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.
Murali
Ramachandran
R
Department 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
Cheng
Xin
X
Berezov
Alan
A
Du
Xiulian
X
Schön
Arnie
A
Freire
Ernesto
E
Xu
Xiaowei
X
Chen
Youhai H
YH
Greene
Mark I
MI
D000495:Allosteric Site / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D011487:Protein Conformation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014364:Tryptophan / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D014364:Tryptophan; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases