4ROL
Deoxyhemoglobin in complex with imidazolylacryloyl derivatives
Summary for 4ROL
| Entry DOI | 10.2210/pdb4rol/pdb |
| Related | 4ROM |
| Descriptor | Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total) |
| Functional Keywords | allosteric, sickle cell disease, hemoglobin, high-affinity, low-affinity, oxygen, oxygen carrying, oxygen transport |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65577.67 |
| Authors | Omar, A.M.,Mahran, M.A.,Ghatge, M.N.,Chowdhury, N.,Bamane, F.H.A.,El-Araby, M.E.,Abdulmalik, O.,Safo, M.K. (deposition date: 2014-10-28, release date: 2015-05-20, Last modification date: 2024-11-20) |
| Primary citation | Omar, A.M.,Mahran, M.A.,Ghatge, M.S.,Chowdhury, N.,Bamane, F.H.,El-Araby, M.E.,Abdulmalik, O.,Safo, M.K. Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents. Org.Biomol.Chem., 13:6353-6370, 2015 Cited by PubMed Abstract: Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds - designated as KAUS (imidazolylacryloyl derivatives) - that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, but showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents. PubMed: 25974708DOI: 10.1039/c5ob00367a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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