5JCT

Crystal Structure of Human Pirin in complex with a Chemical Probe pyrrolidine 24

Summary for 5JCT

• Entry DOI: 10.2210/pdb5jct/pdb
• Descriptor: Pirin, FE (III) ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: cupin, beta-barrel fold, inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O00625
• Total number of polymer chains: 1
• Total formula weight: 35185.60

Authors

Ali, S.,van Montfort, R. (deposition date: 2016-04-15, release date: 2017-01-11, Last modification date: 2024-01-10)

Primary citation

Cheeseman, M.D.,Chessum, N.E.,Rye, C.S.,Pasqua, A.E.,Tucker, M.J.,Wilding, B.,Evans, L.E.,Lepri, S.,Richards, M.,Sharp, S.Y.,Ali, S.,Rowlands, M.,O'Fee, L.,Miah, A.,Hayes, A.,Henley, A.T.,Powers, M.,Te Poele, R.,De Billy, E.,Pellegrino, L.,Raynaud, F.,Burke, R.,van Montfort, R.L.,Eccles, S.A.,Workman, P.,Jones, K.
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
J. Med. Chem., 60:180-201, 2017

PubMed Abstract: Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.

PubMed: 28004573
DOI: 10.1021/acs.jmedchem.6b01055

Experimental method

X-RAY DIFFRACTION (1.73 Å)