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5lby

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Structure of the human quinone reductase 2 (NQO2) in complex with crenolanib

Structural highlights

5lby is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.4Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NQO2_HUMAN The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.^[1]

Publication Abstract from PubMed

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

The target landscape of clinical kinase drugs.,Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, Koenig PA, Reinecke M, Ruprecht B, Petzoldt S, Meng C, Zecha J, Reiter K, Qiao H, Helm D, Koch H, Schoof M, Canevari G, Casale E, Depaolini SR, Feuchtinger A, Wu Z, Schmidt T, Rueckert L, Becker W, Huenges J, Garz AK, Gohlke BO, Zolg DP, Kayser G, Vooder T, Preissner R, Hahne H, Tonisson N, Kramer K, Gotze K, Bassermann F, Schlegl J, Ehrlich HC, Aiche S, Walch A, Greif PA, Schneider S, Felder ER, Ruland J, Medard G, Jeremias I, Spiekermann K, Kuster B Science. 2017 Dec 1;358(6367). pii: 358/6367/eaan4368. doi:, 10.1126/science.aan4368. PMID:29191878^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Calamini B, Santarsiero BD, Boutin JA, Mesecar AD. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. Biochem J. 2008 Jul 1;413(1):81-91. PMID:18254726 doi:10.1042/BJ20071373
↑ Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, Koenig PA, Reinecke M, Ruprecht B, Petzoldt S, Meng C, Zecha J, Reiter K, Qiao H, Helm D, Koch H, Schoof M, Canevari G, Casale E, Depaolini SR, Feuchtinger A, Wu Z, Schmidt T, Rueckert L, Becker W, Huenges J, Garz AK, Gohlke BO, Zolg DP, Kayser G, Vooder T, Preissner R, Hahne H, Tonisson N, Kramer K, Gotze K, Bassermann F, Schlegl J, Ehrlich HC, Aiche S, Walch A, Greif PA, Schneider S, Felder ER, Ruland J, Medard G, Jeremias I, Spiekermann K, Kuster B. The target landscape of clinical kinase drugs. Science. 2017 Dec 1;358(6367). pii: 358/6367/eaan4368. doi:, 10.1126/science.aan4368. PMID:29191878 doi:http://dx.doi.org/10.1126/science.aan4368