4O6W

Peptide-Based Inhibitors of Plk1 Polo-box Domain

Replaces:  4MLU

Summary for 4O6W

• Entry DOI: 10.2210/pdb4o6w/pdb
• Related PRD ID: PRD_001173
• Descriptor: Serine/threonine-protein kinase PLK1, Peptide-Based inhibitor (3 entities in total)
• Functional Keywords: polo box domain, phospho-peptide binding, phosphopeptide, 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: 28220.21

Authors

Qian, W.-J.,Park, J.-E.,Lim, D.C.,Park, S.-Y.,Lee, K.-W.,Yaffe, M.B.,Lee, K.S.,Burke, T.R. (deposition date: 2013-12-23, release date: 2014-12-03, Last modification date: 2025-03-26)

Primary citation

Qian, W.J.,Park, J.E.,Lim, D.,Lai, C.C.,Kelley, J.A.,Park, S.Y.,Lee, K.W.,Yaffe, M.B.,Lee, K.S.,Burke, T.R.
Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in hela cells.
Biopolymers, 102:444-455, 2014

PubMed Abstract: Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(τ)-alkylation of histidine residues already bearing a N(π)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics.

PubMed: 25283071
DOI: 10.1002/bip.22569

Experimental method

X-RAY DIFFRACTION (1.448 Å)