Crystallization of interleukin-18 for structure-based inhibitor design

Acta Crystallogr F Struct Biol Commun. 2015 Jun;71(Pt 6):710-7. doi: 10.1107/S2053230X15006871. Epub 2015 May 20.

Abstract

Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and acquired immune defense, with its activity being modulated in vivo by its naturally occurring antagonist IL-18 binding protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonist or cognate receptor(s) have revealed a conserved binding interface on hIL-18 representing a promising drug target. An important step in this process is obtaining crystals of apo hIL-18 or hIL-18 in complex with small-molecule inhibitors, preferably under low ionic strength conditions. In this study, surface-entropy reduction (SER) and rational protein design were employed to facilitate the crystallization of hIL-18. The results provide an excellent platform for structure-based drug design.

Keywords: cytokines; immune defense; interleukin-18; surface-entropy reduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Crystallization
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Interleukin-18 / chemistry*
  • Interleukin-18 / genetics
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Osmolar Concentration
  • Protein Binding
  • Protein Engineering*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry*
  • Recombinant Fusion Proteins / genetics
  • Surface Properties
  • Thermodynamics

Substances

  • IL18 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • Ligands
  • Recombinant Fusion Proteins
  • interleukin-18 binding protein

Associated data

  • PDB/4XFS
  • PDB/4XFT
  • PDB/4XFU