9C17
Human biliverdin IX beta reductase in complex with NADP and BCT001028
This is a non-PDB format compatible entry.
Summary for 9C17
| Entry DOI | 10.2210/pdb9c17/pdb |
| Related | 9C16 |
| Descriptor | Flavin reductase (NADPH), NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[(4R,7P)-7-(2-chlorophenyl)imidazo[5,1-b][1,3]thiazol-5-yl]benzoic acid, ... (4 entities in total) |
| Functional Keywords | nadp binding, heme degradation, thrombopoiesis, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 23648.99 |
| Authors | |
| Primary citation | Nesbitt, N.M.,Araldi, G.L.,Pennacchia, L.,Marchenko, N.,Assar, Z.,Muzzarelli, K.M.,Thekke Veedu, R.R.,Medel-Lacruz, B.,Lee, E.,Eisenmesser, E.Z.,Kreitler, D.F.,Bahou, W.F. Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo. Nat Commun, 16:3480-3480, 2025 Cited by PubMed Abstract: Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening of unique small molecules retaining the capacity for selective BLVRB inhibition as a novel platelet-enhancing strategy. Two distinct classes of molecules are identified, and NMR spectroscopy and co-crystallization studies confirm binding modes within the BLVRB active site and ring stacking between the nicotinamide moiety of the NADP cofactor. A diazabicyclo derivative displaying minimal off-target promiscuity and excellent bioavailability characteristics promotes megakaryocyte speciation in biphenotypic (erythro/megakaryocyte) cellular models and synergizes with TPO-dependent megakaryocyte formation in hematopoietic stem cells. Upon oral delivery into mice, this inhibitor expands platelet recovery in stress thrombopoietic models with no adverse effects. In this work, we identify and validate a cellular redox inhibitor retaining the potential to selectively promote megakaryocytopoiesis and enhance stress-associated platelet formation in vivo distinct from TPO receptor agonists. PubMed: 40216753DOI: 10.1038/s41467-025-58497-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.63 Å) |
Structure validation
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