1Q4L

GSK-3 Beta complexed with Inhibitor I-5

Summary for 1Q4L

• Entry DOI: 10.2210/pdb1q4l/pdb
• Related: 1PYX 1Q3D 1Q3W 1Q41
• Descriptor: GLYCOGEN SYNTHASE KINASE-3 BETA, 2-CHLORO-5-[4-(3-CHLORO-PHENYL)-2,5-DIOXO-2,5-DIHYDRO-1H-PYRROL-3-YLAMINO]-BENZOIC ACID (3 entities in total)
• Functional Keywords: kinase, insulin pathway, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 94917.30

Authors

Bertrand, J.A.,Thieffine, S.,Vulpetti, A.,Cristiani, C.,Valsasina, B.,Knapp, S.,Kalisz, H.M.,Flocco, M. (deposition date: 2003-08-04, release date: 2003-10-14, Last modification date: 2023-08-16)

Primary citation

Bertrand, J.A.,Thieffine, S.,Vulpetti, A.,Cristiani, C.,Valsasina, B.,Knapp, S.,Kalisz, H.M.,Flocco, M.
Structural Characterization of the Gsk-3Beta Active Site Using Selective and Non-selective ATP-Mimetic Inhibitors
J.Mol.Biol., 333:393-407, 2003

PubMed Abstract: GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.

PubMed: 14529625
DOI: 10.1016/j.jmb.2003.08.031

Experimental method

X-RAY DIFFRACTION (2.77 Å)