4NI1

Quaternary R CO-liganded hemoglobin structure in complex with a thiol containing compound

Summary for 4NI1

• Entry DOI: 10.2210/pdb4ni1/pdb
• Related: 4NI0
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (7 entities in total)
• Functional Keywords: allosteric, tetramer, oxygen transport, relaxed state, tense state, globin fold, red blood cell
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 33454.87

Authors

Safo, M.K.,Meadows, J.,Ko, T.-P.,Nakagawa, A.,Zapol, W. (deposition date: 2013-11-05, release date: 2014-09-17, Last modification date: 2023-09-20)

Primary citation

Nakagawa, A.,Lui, F.E.,Wassaf, D.,Yefidoff-Freedman, R.,Casalena, D.,Palmer, M.A.,Meadows, J.,Mozzarelli, A.,Ronda, L.,Abdulmalik, O.,Bloch, K.D.,Safo, M.K.,Zapol, W.M.
Identification of a Small Molecule that Increases Hemoglobin Oxygen Affinity and Reduces SS Erythrocyte Sickling.
Acs Chem.Biol., 9:2318-2325, 2014

PubMed Abstract: Small molecules that increase the oxygen affinity of human hemoglobin may reduce sickling of red blood cells in patients with sickle cell disease. We screened 38,700 compounds using small molecule microarrays and identified 427 molecules that bind to hemoglobin. We developed a high-throughput assay for evaluating the ability of the 427 small molecules to modulate the oxygen affinity of hemoglobin. We identified a novel allosteric effector of hemoglobin, di(5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4H-1,2,4-triazol-3-yl)disulfide (TD-1). TD-1 induced a greater increase in oxygen affinity of human hemoglobin in solution and in red blood cells than did 5-hydroxymethyl-2-furfural (5-HMF), N-ethylmaleimide (NEM), or diformamidine disulfide. The three-dimensional structure of hemoglobin complexed with TD-1 revealed that monomeric units of TD-1 bound covalently to β-Cys93 and β-Cys112, as well as noncovalently to the central water cavity of the hemoglobin tetramer. The binding of TD-1 to hemoglobin stabilized the relaxed state (R3-state) of hemoglobin. TD-1 increased the oxygen affinity of sickle hemoglobin and inhibited in vitro hypoxia-induced sickling of red blood cells in patients with sickle cell disease without causing hemolysis. Our study indicates that TD-1 represents a novel lead molecule for the treatment of patients with sickle cell disease.

PubMed: 25061917
DOI: 10.1021/cb500230b

Experimental method

X-RAY DIFFRACTION (1.9 Å)