title: Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107.
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.
authors.affiliation: 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
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Alan
authors.initials: A
authors.lastname: Berezov
authors.forename: Xiulian
authors.initials: X
authors.lastname: Du
authors.forename: Arnie
authors.initials: A
authors.lastname: Schön
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: 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
chemical_list: 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