7MX1

PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog

Summary for 7MX1

• Entry DOI: 10.2210/pdb7mx1/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, ACE-PRO-LEU-ALA-SER-TPO, N-[(4S)-4,5-diamino-5-oxopentyl]-10-phenyldecanamide, ... (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: 4
• Total formula weight: 56480.49

Authors

Grant, R.A.,Hymel, D.,Yaffe, M.B.,Burke, T.R. (deposition date: 2021-05-17, release date: 2022-03-30, Last modification date: 2024-10-09)

Primary citation

Hymel, D.,Tsuji, K.,Grant, R.A.,Chingle, R.M.,Kunciw, D.L.,Yaffe, M.B.,Burke Jr., T.R.
Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.
Org.Biomol.Chem., 19:7843-7854, 2021

PubMed Abstract: Targeting protein - protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phospho-dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden "cryptic" pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets.

PubMed: 34346472
DOI: 10.1039/d1ob01120k

Experimental method

X-RAY DIFFRACTION (1.64 Å)