9R1W

PLK1 SURFACE ENTROPY REDUCTION (SER) MUTANT IN COMPLEX WITH THIAZOLIDINONE INHIBITOR COMPOUND 1

This is a non-PDB format compatible entry.

Summary for 9R1W

• Entry DOI: 10.2210/pdb9r1w/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, (2~{Z})-2-cyano-2-[3-ethyl-5-[(~{E})-[2-[methyl-(1-methylpiperidin-4-yl)amino]pyridin-4-yl]iminomethyl]-4-oxidanylidene-1,3-thiazol-2-ylidene]-~{N}-[2,2,2-tris(fluoranyl)ethyl]ethanamide, SULFATE ION, ... (6 entities in total)
• Functional Keywords: surface entropy reduction, ser, small molecule inhibitor, drug design, kinase, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75212.22

Authors

Hillig, R.C.,Schulze, V.K.,Siemeister, G.,Schmitz, A.A.,Eberspaecher, U. (deposition date: 2025-04-28, release date: 2025-11-26, Last modification date: 2025-12-10)

Primary citation

Eberspaecher, U.,Schmitz, A.A.,Siemeister, G.,Bomer, U.,Bandeiras, T.M.,Matias, P.M.,Schulze, V.K.,Hillig, R.C.
Polo-like kinase 1-inhibitor co-complex structures via the surface-entropy reduction approach and a DARPin-assisted approach.
Acta Crystallogr D Struct Biol, 81:718-733, 2025

PubMed Abstract: Polo-like kinase 1 (PLK1) is a major regulator of cell division and has been pursued as a drug target for cancer therapy for a long time. Crystallization of the kinase domain has proven to be exceptionally challenging. Previously, we published a crystallization approach using a PLK1-specific designed ankyrin-repeat protein (DARPin) as a crystallization facilitator. Here, we report an alternative route: crystallization was successful after the introduction of a double mutation which reduced surface entropy and enabled the formation of a new crystal contact. This new PLK1 crystallization system was used to determine the first co-complex crystal structure of the Bayer thiazolidinone lead series, as well as crystal structures with representatives of two competitor inhibitor series. The molecular binding modes of these three inhibitors are analysed and discussed, and the surface-entropy reduction approach is compared with the surface modifications employed by us and others to enable the crystallization of PLK1.

PubMed: 41246821
DOI: 10.1107/S2059798325009325

Experimental method

X-RAY DIFFRACTION (2.2 Å)