8r1p

Pim1 in complex with 6-bromobenzo[d]oxazol-2-amine and Pimtide

spinqualitylabelsall models 8r1p, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8r1p is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.45Å Ligands: SEP, XIP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes. Surprisingly, only the cis-isomer binds upon crystallization of the cis/trans-mixture of the ligands with Pim-1 kinase and the substrate PIMTIDE, the binding mode being largely consistent with that predicted by docking. After crystallization of the exclusively trans-configured derivatives, a markedly different binding mode for the inhibitor and a concomitant rearrangement of the glycine-rich loop is observed, resulting in the ligand being deeply buried in the binding pocket. What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.,Hochban PMM, Heyder L, Heine A, Diederich WE Arch Pharm (Weinheim). 2024 Jun;357(6):e2400094. doi: 10.1002/ardp.202400094. , Epub 2024 Apr 17. PMID:38631036 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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