PDBsum entry 5izf

Transferase

PDB id: 5izf

Contents

Protein chain

338 a.a.

Ligands

6J9-AZ1-DAR-ACA-DAR-NH2

SO4 ×4

Waters ×44

References listed in PDB file

Key reference

• Title: Bifunctional ligands for inhibition of tight-Binding protein-Protein interactions.
• Authors: T.Ivan, E.Enkvist, B.Viira, G.B.Manoharan, G.Raidaru, A.Pflug, K.A.Alam, M.Zaccolo, R.A.Engh, A.Uri.
• Ref.: Bioconjug Chem, 2016, 27, 1900-1910. [DOI no: 10.1021/acs.bioconjchem.6b00293]
• PubMed id: 27389935

Abstract

The acknowledged potential of small-molecule therapeutics targeting disease-related protein-protein interactions (PPIs) has promoted active research in this field. The strategy of using small molecule inhibitors (SMIs) to fight strong (tight-binding) PPIs tends to fall short due to the flat and wide interfaces of PPIs. Here we propose a biligand approach for disruption of strong PPIs. The potential of this approach was realized for disruption of the tight-binding (KD = 100 pM) tetrameric holoenzyme of cAMP-dependent protein kinase (PKA). Supported by X-ray analysis of cocrystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and the PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing a KD value of 3 pM toward PKAc, induced the dissociation of the PKA holoenzyme with a low-nanomolar IC50, whereas the ATP-competitive inhibitor H89 bound to the PKA holoenzyme without disruption of the protein tetramer.