4XX9

Crystal structure of PDK1 in complex with ATP and the PIF-pocket ligand RF4

Summary for 4XX9

• Entry DOI: 10.2210/pdb4xx9/pdb
• Descriptor: 3-phosphoinositide-dependent protein kinase 1, ADENOSINE-5'-TRIPHOSPHATE, (2-{[2-(2,6-dimethylphenoxy)ethyl]sulfanyl}-1H-benzimidazol-1-yl)acetic acid, ... (5 entities in total)
• Functional Keywords: protein kinase, allostery, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36831.85

Authors

Rettenmaier, T.J.,Wells, J.A. (deposition date: 2015-01-29, release date: 2015-10-21, Last modification date: 2024-10-23)

Primary citation

Rettenmaier, T.J.,Fan, H.,Karpiak, J.,Doak, A.,Sali, A.,Shoichet, B.K.,Wells, J.A.
Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking.
J.Med.Chem., 58:8285-8291, 2015

PubMed Abstract: Finding small molecules that target allosteric sites remains a grand challenge for ligand discovery. In the protein kinase field, only a handful of highly selective allosteric modulators have been found. Thus, more general methods are needed to discover allosteric modulators for additional kinases. Here, we use virtual screening against an ensemble of both crystal structures and comparative models to identify ligands for an allosteric peptide-binding site on the protein kinase PDK1 (the PIF pocket). We optimized these ligands through an analog-by-catalog search that yielded compound 4, which binds to PDK1 with 8 μM affinity. We confirmed the docking poses by determining a crystal structure of PDK1 in complex with 4. Because the PIF pocket appears to be a recurring structural feature of the kinase fold, known generally as the helix αC patch, this approach may enable the discovery of allosteric modulators for other kinases.

PubMed: 26443011
DOI: 10.1021/acs.jmedchem.5b01216

Experimental method

X-RAY DIFFRACTION (1.4 Å)