6XD9
Carbonmonoxy hemoglobin in complex with the antisickling agent 2-hydroxy-6-((6-(hydroxymethyl)pyridin-2-yl)methoxy)benzaldehyde (VZHE039)
Summary for 6XD9
| Entry DOI | 10.2210/pdb6xd9/pdb |
| Descriptor | Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (6 entities in total) |
| Functional Keywords | hemoglobin, aromatic aldehyde, antisickling, allosteric effector, oxygen transport |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65149.64 |
| Authors | Pagare, P.P.,Safo, M.K.,Musayev, F.N. (deposition date: 2020-06-10, release date: 2020-12-23, Last modification date: 2024-12-25) |
| Primary citation | Abdulmalik, O.,Pagare, P.P.,Huang, B.,Xu, G.G.,Ghatge, M.S.,Xu, X.,Chen, Q.,Anabaraonye, N.,Musayev, F.N.,Omar, A.M.,Venitz, J.,Zhang, Y.,Safo, M.K. VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Sci Rep, 10:20277-20277, 2020 Cited by PubMed Abstract: Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O-dependent and O-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate. PubMed: 33219275DOI: 10.1038/s41598-020-77171-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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