5ACK

Human PDK1 Kinase Domain in Complex with Allosteric Compound 7 Bound to the PIF-Pocket

Summary for 5ACK

• Entry DOI: 10.2210/pdb5ack/pdb
• Descriptor: 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1, ADENOSINE-5'-TRIPHOSPHATE, 1-(4-CHLOROPHENETHYL)-2-(2-CHLOROPHENYL)-6-OXOPIPERIDINE-3-CARBOXYLIC ACID, ... (7 entities in total)
• Functional Keywords: transferase, kinase, allostery, virtual screening, pharmacophore, multicomponent reaction
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 36591.36

Authors

Schulze, J.O.,Kroon, E.,Doemling, A.,Biondi, R.M. (deposition date: 2015-08-17, release date: 2015-10-21, Last modification date: 2024-01-10)

Primary citation

Kroon, E.,Schulze, J.O.,Suss, E.,Camacho, C.J.,Biondi, R.M.,Domling, A.
Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods.
Angew.Chem.Int.Ed.Engl., 54:13933-, 2015

PubMed Abstract: The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth-factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells. ANCHOR.QUERY software was used to discover a potent allosteric PDK1 kinase modulator. Using a recently published PDK1 compound as a template, several new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERY approach. Our results are significant because the outlined approach allows rapid and efficient scaffold hopping from known molecules into new easily accessible and biologically active ones. Based on increasing interest in allosteric-site drug discovery, we foresee many potential applications for this approach.

PubMed: 26385475
DOI: 10.1002/ANIE.201506310

Experimental method

X-RAY DIFFRACTION (1.24 Å)