7UVB
CRYSTAL STRUCTURE OF CARBONMONOXY HEMOGLOBIN S (LIGANDED SICKLE CELL HEMOGLOBIN) COMPLEXED WITH GBT021601
Summary for 7UVB
| Entry DOI | 10.2210/pdb7uvb/pdb |
| Descriptor | Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total) |
| Functional Keywords | metalloprotein, globulin, oxygen transport |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65379.99 |
| Authors | Partridge, J.R.,Kaya, E.,Xu, Q.,Li, Z.,Strutt, S.C.,Cathers, B.E. (deposition date: 2022-04-29, release date: 2023-04-05, Last modification date: 2023-10-25) |
| Primary citation | Dufu, K.,Alt, C.,Strutt, S.,Partridge, J.,Tang, T.,Siu, V.,Liao-Zou, H.,Rademacher, P.,Williams, A.T.,Muller, C.R.,Geng, X.,Pochron, M.P.,Dang, A.N.,Cabrales, P.,Li, Z.,Oksenberg, D.,Cathers, B.E. GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model. Br.J.Haematol., 202:173-183, 2023 Cited by PubMed Abstract: The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601. PubMed: 36960712DOI: 10.1111/bjh.18771 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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