PDBsum entry 5izf

Transferase

PDB id: 5izf

Contents

Protein chain

338 a.a.

Ligands

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

SO4 ×4

Waters ×44

PDB id:

5izf

Name:

Transferase

Title:

Complex of pka with the bisubstrate protein kinase inhibitor arc-1408

Structure:

Camp-dependent protein kinase catalytic subunit alpha. Chain: a. Synonym: pka c-alpha. Engineered: yes. 6j9-zeu-dar-aca-dar-nh2. Chain: e. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prkaca, pkaca. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.10Å R-factor: 0.232 R-free: 0.270

Authors:

A.Pflug,E.Enkvist,A.Uri,R.A.Engh

Key ref:

T.Ivan et al. (2016). Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions. Bioconjug Chem, 27, 1900-1910. PubMed id: 27389935 DOI: 10.1021/acs.bioconjchem.6b00293

Date:

25-Mar-16 Release date: 20-Jul-16

Protein chain

P17612  (KAPCA_HUMAN) -  cAMP-dependent protein kinase catalytic subunit alpha from Homo sapiens

Seq: 351 a.a.

Struc: 338 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.11.11 - cAMP-dependent protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.bioconjchem.6b00293

Bioconjug Chem 27:1900-1910 (2016)

PubMed id: 27389935

Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions.

T.Ivan, E.Enkvist, B.Viira, G.B.Manoharan, G.Raidaru, A.Pflug, K.A.Alam, M.Zaccolo, R.A.Engh, A.Uri.

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.