3RQ7

Polo-like kinase 1 Polo box domain in complex with a C6H5(CH2)8-derivatized peptide inhibitor

Summary for 3RQ7

• Entry DOI: 10.2210/pdb3rq7/pdb
• Related: 1Q4K 1UMW 3BZI 3C5L 3FVH 3HIK
• Related PRD ID: PRD_000794
• Descriptor: Serine/threonine-protein kinase PLK1, C6H5(CH2)8-derivatized peptide inhibitor (3 entities in total)
• Functional Keywords: phosphopeptide binding domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P53350
• Total number of polymer chains: 2
• Total formula weight: 28131.10

Authors

Liu, F.,Park, J.-E.,Qian, W.-J.,Lim, D.C.,Graber, M.,Berg, T.,Yaffe, M.B.,Lee, K.S.,Burke Jr., T.R. (deposition date: 2011-04-27, release date: 2011-07-20, Last modification date: 2024-10-16)

Primary citation

Liu, F.,Park, J.E.,Qian, W.J.,Lim, D.,Graber, M.,Berg, T.,Yaffe, M.B.,Lee, K.S.,Burke, T.R.
Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel.
Nat.Chem.Biol., 7:595-601, 2011

PubMed Abstract: We obtained unanticipated synthetic byproducts from alkylation of the δ(1) nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C(6)H(5)(CH(2))(8)- group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents.

PubMed: 21765407
DOI: 10.1038/nchembio.614

Experimental method

X-RAY DIFFRACTION (1.55 Å)