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4WHH

A New Class of Peptidomimetics Targeting the Polo-box Domain of Polo-like kinase 1

Summary for 4WHH
Entry DOI10.2210/pdb4whh/pdb
Related4WHK 4WHL
Related PRD IDPRD_002127
DescriptorSerine/threonine-protein kinase PLK1, C6H5(CH2)8-DERIVATIZED PEPTIDE INHIBITOR, SULFATE ION, ... (4 entities in total)
Functional Keywordspolo-like kinase, inhibitor, peptide derivative, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight28292.13
Authors
Bang, J.K. (deposition date: 2014-09-22, release date: 2014-12-03, Last modification date: 2023-11-15)
Primary citationAhn, M.,Han, Y.H.,Park, J.E.,Kim, S.,Lee, W.C.,Lee, S.J.,Gunasekaran, P.,Cheong, C.,Shin, S.Y.,Kim, H.Y.,Ryu, E.K.,Murugan, R.N.,Kim, N.H.,Bang, J.K.
A new class of peptidomimetics targeting the polo-box domain of polo-like kinase 1.
J.Med.Chem., 58:294-304, 2015
Cited by
PubMed Abstract: Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organic moieties, leading to the identification of the peptidomimetic 8 (AB-103) series with high binding affinity and selectivity. To evaluate the bioavailability of short peptidomimetic ligands, PEGylated 8 series were synthesized and incubated with HeLa cells to test for cellular uptake, antiproliferative activity, and Plk1 kinase inhibition. Finally, crystallographic studies of the Plk1 PBD in complex with peptidomimetics 8 and 22 (AB-103-5) revealed the presence of two hydrogen bond interactions responsible for their high binding affinity and selectivity.
PubMed: 25347203
DOI: 10.1021/jm501147g
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.9 Å)
Structure validation

226707

數據於2024-10-30公開中

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