6H1H
Crystal structure of human Pirin in complex with compound 7 (PLX4720)
Summary for 6H1H
| Entry DOI | 10.2210/pdb6h1h/pdb |
| Descriptor | Pirin, FE (III) ION, [3-azanyl-2,6-bis(fluoranyl)phenyl]-(5-chloranyl-1~{H}-pyrrolo[2,3-b]pyridin-3-yl)methanone, ... (6 entities in total) |
| Functional Keywords | transcriptional coregulator, quercetin 2, 3-dioxygenase, inhibitor, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33205.61 |
| Authors | Ali, S.,Le Bihan, Y.V.,van Montfort, R.L.M. (deposition date: 2018-07-11, release date: 2018-11-28, Last modification date: 2024-01-17) |
| Primary citation | Meyers, J.,Chessum, N.E.A.,Ali, S.,Mok, N.Y.,Wilding, B.,Pasqua, A.E.,Rowlands, M.,Tucker, M.J.,Evans, L.E.,Rye, C.S.,O'Fee, L.,Le Bihan, Y.V.,Burke, R.,Carter, M.,Workman, P.,Blagg, J.,Brown, N.,van Montfort, R.L.M.,Jones, K.,Cheeseman, M.D. Privileged Structures and Polypharmacology within and between Protein Families. ACS Med Chem Lett, 9:1199-1204, 2018 Cited by PubMed Abstract: Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 () and the pirin ligand CCT245232 (), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries. PubMed: 30613326DOI: 10.1021/acsmedchemlett.8b00364 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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