8R1P

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

Summary for 8R1P

• Entry DOI: 10.2210/pdb8r1p/pdb
• Related: 7QB2 7QFM 7Z6U 8AFR 8R0H 8R0Q 8R0W 8R0Y 8R10 8R18 8R1K 8R1N
• Descriptor: Serine/threonine-protein kinase pim-1, Pimtide, 4-(4-aminostyryl)benzoic acid, ... (4 entities in total)
• Functional Keywords: serine kinase, kinase, complex, pim1, pim, pim-1, inhibitor, tumorigenisis, cancer, pimtide, proto oncogen, atp, phosphorylation, apoptosis, cell cycle, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 37502.60

Authors

Hochban, P.M.M.,Heine, A.,Diederich, W.E. (deposition date: 2023-11-02, release date: 2024-03-20, Last modification date: 2024-10-16)

Primary citation

Hochban, P.M.M.,Heyder, L.,Heine, A.,Diederich, W.E.
What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.
Arch Pharm, 357:e2400094-e2400094, 2024

PubMed Abstract: 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.

PubMed: 38631036
DOI: 10.1002/ardp.202400094

Experimental method

X-RAY DIFFRACTION (2.45 Å)