9C18

Human biliverdin IX beta reductase in complex with NADP in space group P1

9C18 の概要

• エントリーDOI: 10.2210/pdb9c18/pdb
• 関連するPDBエントリー: 9C16 9C17
• 分子名称: Flavin reductase (NADPH), NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• 機能のキーワード: nadp binding, heme degradation, thrombopoiesis, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46588.36

構造登録者

Kreitler, D.F. (登録日: 2024-05-28, 公開日: 2025-04-23)

主引用文献

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

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: 40216753
DOI: 10.1038/s41467-025-58497-9

実験手法

X-RAY DIFFRACTION (1.9 Å)