8CRC

Structure of human Plk1 PBD in complex with Allopole-A

Summary for 8CRC

• Entry DOI: 10.2210/pdb8crc/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, GLYCEROL, 7-chloro-4-(cyclopropylmethyl)-1-thioxo-2,4-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one, ... (4 entities in total)
• Functional Keywords: kinase, serine/threonine protein kinase, small molecule, allosteric inhibitor, cell cycle, localization, cell division, mitosis, nucleus, phosphoprotein, transferase, phosphopeptide binding domain, transferase-inhibitor complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 26773.02

Authors

Kirsch, K.,Park, J.E.,Lee, K.S. (deposition date: 2023-03-08, release date: 2023-08-16, Last modification date: 2023-08-30)

Primary citation

Park, J.E.,Kirsch, K.,Lee, H.,Oliva, P.,Ahn, J.I.,Ravishankar, H.,Zeng, Y.,Fox, S.D.,Kirby, S.A.,Badhwar, P.,Andresson, T.,Jacobson, K.A.,Lee, K.S.
Specific inhibition of an anticancer target, polo-like kinase 1, by allosterically dismantling its mechanism of substrate recognition.
Proc.Natl.Acad.Sci.USA, 120:e2305037120-e2305037120, 2023

PubMed Abstract: Polo-like kinase 1 (Plk1) is considered an attractive target for anticancer therapy. Over the years, studies on the noncatalytic polo-box domain (PBD) of Plk1 have raised the expectation of generating highly specific protein-protein interaction inhibitors. However, the molecular nature of the canonical PBD-dependent interaction, which requires extensive water network-mediated interactions with its phospholigands, has hampered efforts to identify small molecules suitable for Plk1 PBD drug discovery. Here, we report the identification of the first allosteric inhibitor of Plk1 PBD, called Allopole, a prodrug that can disrupt intracellular interactions between PBD and its cognate phospholigands, delocalize Plk1 from centrosomes and kinetochores, and induce mitotic block and cancer cell killing. At the structural level, its unmasked active form, Allopole-A, bound to a deep Trp-Phe-lined pocket occluded by a latch-like loop, whose adjoining region was required for securely retaining a ligand anchored to the phospho-binding cleft. Allopole-A binding completely dislodged the L2 loop, an event that appeared sufficient to trigger the dissociation of a phospholigand and inhibit PBD-dependent Plk1 function during mitosis. Given Allopole's high specificity and antiproliferative potency, this study is expected to open an unexplored avenue for developing Plk1 PBD-specific anticancer therapeutic agents.

PubMed: 37603740
DOI: 10.1073/pnas.2305037120

Experimental method

X-RAY DIFFRACTION (1.65 Å)