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Structural anomalies in a published NMR-derived structure of IRAK-M

Hessel Poelman1, Hans Ippel2, Berke Gürkan3

  • 1Amsterdam UMC, University of Amsterdam, Medical Biochemistry, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands.

Journal of Molecular Graphics & Modelling
|November 27, 2021
PubMed

Insights

The Toll-Like Receptor and Interleukin-1 Receptor (IL1-R) pathway relies on MyD88 and IL-1R Associated Kinases (IRAKs). A new study identified structural anomalies in the IRAK-M death domain NMR structure (5UKE), proposing a refined model for better accuracy.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Immunology

Background:

  • Toll-Like Receptor (TLR) and Interleukin-1 Receptor (IL1-R) signaling pathways are crucial for innate immunity.
  • These pathways involve MyD88 adaptor protein and IL-1R Associated Kinases (IRAKs), forming the Myddosome complex.
  • Understanding the structure of IRAK-M death domain is vital for elucidating Myddosome assembly and signaling specificity.

Purpose of the Study:

  • To analyze the structural integrity of the IRAK-M death domain monomer structure (PDBid: 5UKE) determined by NMR.
  • To investigate potential structural anomalies in 5UKE that could impact downstream modeling and analysis.
  • To develop an improved homology model of the IRAK-M death domain based on high-resolution X-ray structures.

Main Methods:

  • Analysis of the IRAK-M death domain NMR structure (5UKE) using structure validation tools.
  • Comparison of 5UKE with homologous high-resolution X-ray crystal structures.
  • Homology modeling using Yasara, based on two high-resolution crystal structures of death domains.

Main Results:

  • Identification of significant structural anomalies in the 5UKE NMR structure, including packing issues, frayed helices, and improbable side chain conformations.
  • Demonstration that homology models based on 5UKE exhibit structural problems like disallowed torsion angles.
  • Development of an alternative homology model for the IRAK-M death domain that better aligns with known structural data and deposited chemical shift data.

Conclusions:

  • The IRAK-M death domain NMR structure (5UKE) contains notable structural inaccuracies.
  • A refined homology model provides a more reliable structural representation of the IRAK-M death domain.
  • This improved model is essential for accurate docking studies and understanding IRAK-M's role in Myddosome assembly and signaling selectivity.
Keywords:
5UKEDALIHomology modelingIRAK-MMyddosomeNMRStructure validationTALOS-NWHAT_CHECKYasara

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