6AK2

Crystal structure of the syntenin PDZ1 domain in complex with the peptide inhibitor KSL-128018

6AK2 の概要

• エントリーDOI: 10.2210/pdb6ak2/pdb
• 分子名称: Syntenin-1, peptide inhibitor KSL-128018 (3 entities in total)
• 機能のキーワード: signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 19482.44

構造登録者

Jin, Z.Y.,Park, J.H.,Yun, J.H.,Haugaard-Kedstrom, L.M.,Lee, W.T. (登録日: 2018-08-29, 公開日: 2019-09-04, 最終更新日: 2024-10-16)

主引用文献

Haugaard-Kedstrom, L.M.,Clemmensen, L.S.,Sereikaite, V.,Jin, Z.,Fernandes, E.F.A.,Wind, B.,Abalde-Gil, F.,Daberger, J.,Vistrup-Parry, M.,Aguilar-Morante, D.,Leblanc, R.,Egea-Jimenez, A.L.,Albrigtsen, M.,Jensen, K.E.,Jensen, T.M.T.,Ivarsson, Y.,Vincentelli, R.,Hamerlik, P.,Andersen, J.H.,Zimmermann, P.,Lee, W.,Stromgaard, K.
A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma.
J.Med.Chem., 64:1423-1434, 2021

PubMed Abstract: Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.

PubMed: 33502198
DOI: 10.1021/acs.jmedchem.0c00382

実験手法

X-RAY DIFFRACTION (1.868 Å)