6ak2
From Proteopedia
Crystal structure of the syntenin PDZ1 domain in complex with the peptide inhibitor KSL-128018
Structural highlights
FunctionSDCB1_RAT Multifunctional adapter protein involved in diverse array of functions including trafficking of transmembrane proteins, neuro and immunomodulation, exosome biogenesis, and tumorigenesis. Positively regulates TGFB1-mediated SMAD2/3 activation and TGFB1-induced epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types. May increase TGFB1 signaling by enhancing cell-surface expression of TGFR1 by preventing the interaction between TGFR1 and CAV1 and subsequent CAV1-dependent internalization and degradation of TGFR1. In concert with SDC1/4 and PDCD6IP, regulates exosome biogenesis. Regulates migration, growth, proliferation, and cell cycle progression in a variety of cancer types. In adherens junctions may function to couple syndecans to cytoskeletal proteins or signaling components. Seems to couple transcription factor SOX4 to the IL-5 receptor (IL5RA). May also play a role in vesicular trafficking. Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway.[UniProtKB:O00560] Publication Abstract from PubMedDespite 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. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma.,Haugaard-Kedstrom LM, Clemmensen LS, Sereikaite V, Jin Z, Fernandes EFA, Wind B, Abalde-Gil F, Daberger J, Vistrup-Parry M, Aguilar-Morante D, Leblanc R, Egea-Jimenez AL, Albrigtsen M, Jensen KE, Jensen TMT, Ivarsson Y, Vincentelli R, Hamerlik P, Andersen JH, Zimmermann P, Lee W, Stromgaard K J Med Chem. 2021 Feb 11;64(3):1423-1434. doi: 10.1021/acs.jmedchem.0c00382. Epub , 2021 Jan 27. PMID:33502198[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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