8EGI
X-ray structure of carbonmonoxy hemoglobin in complex with VZHE039-NO
Summary for 8EGI
| Entry DOI | 10.2210/pdb8egi/pdb |
| Descriptor | Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (6 entities in total) |
| Functional Keywords | hemoglobin, sickle cell disease, antisickling, nitric oxide, oxygen equilibrium curve, oxygen transport |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65764.42 |
| Authors | Donkor, A.K.,Musayev, F.N.,Safo, M.K. (deposition date: 2022-09-12, release date: 2022-11-16, Last modification date: 2024-11-13) |
| Primary citation | Huang, B.,Ghatge, M.S.,Donkor, A.K.,Musayev, F.N.,Deshpande, T.M.,Al-Awadh, M.,Alhashimi, R.T.,Zhu, H.,Omar, A.M.,Telen, M.J.,Zhang, Y.,McMahon, T.J.,Abdulmalik, O.,Safo, M.K. Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease. Molecules, 27:-, 2022 Cited by PubMed Abstract: Sickle cell disease (SCD) is caused by a single-point mutation, and the ensuing deoxygenation-induced polymerization of sickle hemoglobin (HbS), and reduction in bioavailability of vascular nitric oxide (NO), contribute to the pathogenesis of the disease. In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits. PubMed: 36296435DOI: 10.3390/molecules27206835 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
