The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding

Jordan H. Chill, Sabine R. Quadt, Rina Levy, Gideon Schreiber, Jacob Anglister

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution, reveals the molecular basis for IFN binding. The atypical perpendicular orientation of its two fibronectin domains explains the lack of C domain involvement in ligand binding. A model of the IFNAR2-EC/IFNα2 complex based on double mutant cycle-derived constraints uncovers an extensive and predominantly aliphatic hydrophobic patch on the receptor that interacts with a matching hydrophobic surface of IFNα2. An adjacent motif of alternating charged side chains guides the two proteins into a tight complex. The binding interface may account for crossreactivity and ligand specificity of the receptor. This molecular description of IFN binding should be invaluable for study and design of IFN-based biomedical agents.

Original languageEnglish
Pages (from-to)791-802
Number of pages12
JournalStructure
Volume11
Issue number7
DOIs
StatePublished - 1 Jul 2003
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Vitali Tugarinov for assistance with NMR experiments and Dr. Tali Scherf for spectrometer assistance. We are also indebted to Dr. Miri Eisenstein for several helpful discussions on modeling aspects of this work and Prof. Fred Naider for critical reading of this manuscript. This work was supported by the National Institutes of Health and the Israel Academy of Sciences (to J.A.). J.A. is the Dr. Joseph and Ruth Owades Professor of Chemistry.

Funding

We thank Dr. Vitali Tugarinov for assistance with NMR experiments and Dr. Tali Scherf for spectrometer assistance. We are also indebted to Dr. Miri Eisenstein for several helpful discussions on modeling aspects of this work and Prof. Fred Naider for critical reading of this manuscript. This work was supported by the National Institutes of Health and the Israel Academy of Sciences (to J.A.). J.A. is the Dr. Joseph and Ruth Owades Professor of Chemistry.

FundersFunder number
National Institutes of Health
Academy of Leisure Sciences

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