7MSO

Crystal Structure of Polo Box Domain in Complex with Cyclic Peptide Inhibitor

Summary for 7MSO

• Entry DOI: 10.2210/pdb7mso/pdb
• Related PRD ID: PRD_002479
• Descriptor: Serine/threonine-protein kinase PLK1, Cyclic Peptide Inhibitor ZO1-GLN-SER-TPO-45W-MLL (3 entities in total)
• Functional Keywords: phosphopeptide binding domain, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 56279.84

Authors

Lim, D.C.,Yaffe, M.B. (deposition date: 2021-05-11, release date: 2022-03-02, Last modification date: 2024-07-10)

Primary citation

Ryu, S.,Park, J.E.,Ham, Y.J.,Lim, D.C.,Kwiatkowski, N.P.,Kim, D.H.,Bhunia, D.,Kim, N.D.,Yaffe, M.B.,Son, W.,Kim, N.,Choi, T.I.,Swain, P.,Kim, C.H.,Lee, J.Y.,Gray, N.S.,Lee, K.S.,Sim, T.
Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1.
J.Med.Chem., 65:1915-1932, 2022

PubMed Abstract: The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both and possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with reveals that the 3-(trifluoromethyl)benzoyl group in interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, , a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of . Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.

PubMed: 35029981
DOI: 10.1021/acs.jmedchem.1c01359

Experimental method

X-RAY DIFFRACTION (1.85 Å)