TY - JOUR
T1 - Structural anomalies in a published NMR-derived structure of IRAK-M
AU - Poelman, Hessel
AU - Ippel, Hans
AU - Gürkan, Berke
AU - Boelens, Rolf
AU - Vriend, Gert
AU - Veer, Cornelis van ‘t
AU - Lutgens, Esther
AU - Nicolaes, Gerry A. F.
N1 - Funding Information: EL and HP would like to acknowledge financial support from the ERC ( CD40In , nr 681493 ) awarded to EL. Publisher Copyright: © 2021
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Signaling by Toll-Like Receptors and the Interleukin-1 Receptor (IL1-R) involves intracellular binding of MyD88, followed by assembly of IL1-R Associated Kinases (IRAKs) into the so-called Myddosome. Using NMR, Nechama et al. determined the structure of the IRAK-M death domain monomer (PDBid: 5UKE). With this structure, they performed a docking study to model the location of IRAK-M in the Myddosome. Based on this, they present a molecular basis for selectivity of IRAK-M towards IRAK1 over IRAK2 binding. When we attempted to use 5UKE as a homology modeling template, we noticed that our 5UKE-based models had structural issues, such as disallowed torsion angles and solvent exposed tryptophans. We therefore analyzed the NMR ensemble of 5UKE using structure validation tools and we compared 5UKE with homologous high-resolution X-ray structures. We identified several structural anomalies in 5UKE, including packing issues, frayed helices and improbable side chain conformations. We used Yasara to build a homology model, based on two high resolution death domain crystal structures, as an alternative model for the IRAK-M death domain (atomic coordinates, modeling details and validation are available at https://swift.cmbi.umcn.nl/gv/service/5uke/). Our model agrees better with known death domain structure information than 5UKE and also with the chemical shift data that was deposited for 5UKE.
AB - Signaling by Toll-Like Receptors and the Interleukin-1 Receptor (IL1-R) involves intracellular binding of MyD88, followed by assembly of IL1-R Associated Kinases (IRAKs) into the so-called Myddosome. Using NMR, Nechama et al. determined the structure of the IRAK-M death domain monomer (PDBid: 5UKE). With this structure, they performed a docking study to model the location of IRAK-M in the Myddosome. Based on this, they present a molecular basis for selectivity of IRAK-M towards IRAK1 over IRAK2 binding. When we attempted to use 5UKE as a homology modeling template, we noticed that our 5UKE-based models had structural issues, such as disallowed torsion angles and solvent exposed tryptophans. We therefore analyzed the NMR ensemble of 5UKE using structure validation tools and we compared 5UKE with homologous high-resolution X-ray structures. We identified several structural anomalies in 5UKE, including packing issues, frayed helices and improbable side chain conformations. We used Yasara to build a homology model, based on two high resolution death domain crystal structures, as an alternative model for the IRAK-M death domain (atomic coordinates, modeling details and validation are available at https://swift.cmbi.umcn.nl/gv/service/5uke/). Our model agrees better with known death domain structure information than 5UKE and also with the chemical shift data that was deposited for 5UKE.
KW - 5UKE
KW - DALI
KW - Homology modeling
KW - IRAK-M
KW - Myddosome
KW - NMR
KW - Structure validation
KW - TALOS-N
KW - WHAT_CHECK
KW - Yasara
UR - http://www.scopus.com/inward/record.url?scp=85119656216&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jmgm.2021.108061
DO - https://doi.org/10.1016/j.jmgm.2021.108061
M3 - Article
C2 - 34837785
SN - 1093-3263
VL - 111
JO - Journal of molecular graphics & modelling
JF - Journal of molecular graphics & modelling
M1 - 108061
ER -