Peptidomimetics with full antagonistic effect stabilize insulin
receptor in novel conformation

a 2024

Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation

POLÁK, Martin, Irena SELICHAROVA, Michal GRZYBEK, Uenal COSKUN, Jiri JIRACEK et. al.

Basic information

Original name

Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation

Authors

POLÁK, Martin, Irena SELICHAROVA, Michal GRZYBEK, Uenal COSKUN, Jiri JIRACEK and Jiří NOVÁČEK

Edition

Final iNEXT-discovery consortium meeting and 4 th symposium on recent advances in cryo-EM, 2024

Other information

Type of outcome

Konferenční abstrakt

Confidentiality degree

není předmětem státního či obchodního tajemství

ISBN

978-80-280-0560-3

Abstract

V originále

The human insulin receptor (IR) is one of the most studied receptor tyrosine kinases (RTKs). Binding of the signal molecule to the extracellular part of RTKs initiates receptor dimerization which triggers autophosphorylation on the intracellular part of the receptor. Unlike most RTKs, IR forms a disulfide bond stabilized dimer already in the apo-form. Therefore, an autoinhibitory mechanism must exist to prevent non-receptor activation of the signaling pathway. We have studied the structural changes of the insulin receptor ectodomain in vitro caused by 3 peptidomimetics: adamantane-derived mimetic (Ada), trimesic acid-derived mimetic (Trim) and S661, which were shown to be full insulin antagonists. We have used single particle electron cryo-microcopy (cryo-EM) to describe the mechanism of insulin receptor inhibition by these compounds. Our cryo-EM structures reveal that the studied antagonists cross-link L1 and FnIII-1’ domains of the insulin receptor, therefore stabilizing the Π shape structure in which membrane proximal regions of FnIII-3 and FnIII-3’ are separated by 115 Å, thus preventing autophosphorylation in the intracellular domains of the receptor. The head of the dimer (L1 to FnIII-1’ and L1’ to FnIII-1) is wider than in the case of insulin-IR and forms a shape resembling goggles. Remarkably, we do not observe α-CT helix densities in our cryo- EM maps. In addition, multiple interaction interfaces are observed between L1 and FnIII-2 domains which provide indication for elucidation of receptor activation mechanism.

Citovat

POLÁK, Martin, Irena SELICHAROVA, Michal GRZYBEK, Uenal COSKUN, Jiri JIRACEK and Jiří NOVÁČEK. Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation. In Final iNEXT-discovery consortium meeting and 4 th symposium on recent advances in cryo-EM. 2024. ISBN 978-80-280-0560-3.

@proceedings{2411989,
   author = {Polák, Martin and Selicharova, Irena and Grzybek, Michal and Coskun, Uenal and Jiracek, Jiri and Nováček, Jiří},
   booktitle = {Final iNEXT-discovery consortium meeting and 4 th symposium on recent advances in cryo-EM},
   isbn = {978-80-280-0560-3},
   title = {Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation},
   year = {2024}
}

TY  - CONF
ID  - 2411989
AU  - Polák, Martin - Selicharova, Irena - Grzybek, Michal - Coskun, Uenal - Jiracek, Jiri - Nováček, Jiří
PY  - 2024
TI  - Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation
SN  - 9788028005603
N2  - The human insulin receptor (IR) is one of the most studied receptor tyrosine kinases (RTKs). Binding of the signal molecule to the extracellular part of RTKs initiates receptor dimerization which triggers autophosphorylation on the intracellular part of the receptor. Unlike most RTKs, IR forms a disulfide bond stabilized dimer already in the apo-form. Therefore, an autoinhibitory mechanism must exist to prevent non-receptor activation of the signaling pathway. We have studied the structural changes of the insulin receptor ectodomain in vitro caused by 3 peptidomimetics: adamantane-derived mimetic (Ada), trimesic acid-derived mimetic (Trim) and S661, which were shown to be full insulin antagonists. We have used single particle electron cryo-microcopy (cryo-EM) to describe the mechanism of insulin receptor inhibition by these compounds. Our cryo-EM structures reveal that the studied antagonists cross-link L1 and FnIII-1’ domains of the insulin receptor, therefore stabilizing the Π shape structure in which membrane proximal regions of FnIII-3 and FnIII-3’ are separated by 115 Å, thus preventing autophosphorylation in the intracellular domains of the receptor. The head of the dimer (L1 to FnIII-1’ and L1’ to FnIII-1) is wider than in the case of insulin-IR and forms a shape resembling goggles. Remarkably, we do not observe α-CT helix densities in our cryo- EM maps. In addition, multiple interaction interfaces are observed between L1 and FnIII-2 domains which provide indication for elucidation of receptor activation mechanism.
ER  -

POLÁK, Martin, Irena SELICHAROVA, Michal GRZYBEK, Uenal COSKUN, Jiri JIRACEK and Jiří NOVÁČEK. Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation. In \textit{Final iNEXT-discovery consortium meeting and 4 th symposium on recent advances in cryo-EM}. 2024. ISBN~978-80-280-0560-3.

Detailed Information on Publication Record