9c16

Human biliverdin IX beta reductase in complex with NADP and BCT002029

spinqualitylabelsall models 9c16, resolution 1.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9c16 is a 1 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 1.58Å Ligands: A1ATI, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BLVRB_HUMAN Broad specificity oxidoreductase that catalyzes the NADPH-dependent reduction of a variety of flavins, such as riboflavin, FAD or FMN, biliverdins, methemoglobin and PQQ (pyrroloquinoline quinone). Contributes to heme catabolism and metabolizes linear tetrapyrroles. Can also reduce the complexed Fe(3+) iron to Fe(2+) in the presence of FMN and NADPH. In the liver, converts biliverdin to bilirubin. Publication Abstract from PubMed Biliverdin IXbeta 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. Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo.,Nesbitt NM, Araldi GL, Pennacchia L, Marchenko N, Assar Z, Muzzarelli KM, Thekke Veedu RR, Medel-Lacruz B, Lee E, Eisenmesser EZ, Kreitler DF, Bahou WF Nat Commun. 2025 Apr 11;16(1):3480. doi: 10.1038/s41467-025-58497-9. PMID:40216753 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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