6AX4

Plk-1 polo-box domain in complex with histidine N(tau)-cyclized Macrocycle 5b.

Summary for 6AX4

• Entry DOI: 10.2210/pdb6ax4/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, histidine N(tau)-cyclized Macrocycle 5b, AMYLAMINE, ... (4 entities in total)
• Functional Keywords: macrocyclic phosphopeptide, mitotic kinase. polo-box domain, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28236.26

Authors

Grant, R.A.,Hymel, D.,Yaffe, M.B.,Burke, T.R. (deposition date: 2017-09-06, release date: 2018-09-12, Last modification date: 2023-11-15)

Primary citation

Hymel, D.,Grant, R.A.,Tsuji, K.,Yaffe, M.B.,Burke Jr., T.R.
Histidine N( tau )-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors.
Bioorg. Med. Chem. Lett., 28:3202-3205, 2018

PubMed Abstract: Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLHSpT (2a) (where H indicates the presence of a -(CH)Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal "Pro-Leu" motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.

PubMed: 30174151
DOI: 10.1016/j.bmcl.2018.08.018

Experimental method

X-RAY DIFFRACTION (1.45 Å)