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Natural Conformational Sampling of Human TNF? Visualized by Double Electron-Electron Resonance.

ABSTRACT: Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor ? trimer. We suggest a previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be rotated and tilted outward at the tip end, leading to a breaking of the trimerous symmetry and distortion at a receptor-binding interface. The new structure offers opportunities to modulate the biological activity of tumor necrosis factor ? through stabilization of the distorted trimer with small molecules.

SUBMITTER: Carrington B

PROVIDER: S-EPMC5529296 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Natural Conformational Sampling of Human TNFα Visualized by Double Electron-Electron Resonance.

Carrington Bruce B Myers William K WK Horanyi Peter P Calmiano Mark M Lawson Alastair D G ADG

Biophysical journal 20170701 2

Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor α trimer. We suggest a previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be ro ...[more]

PMID: 28746848

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