期刊
JOURNAL OF STRUCTURAL BIOLOGY
卷 194, 期 3, 页码 446-450出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2016.04.003
关键词
Crystal structure; Hemoglobin; R-state; Allosteric; Sickle cell disease; Mutation
资金
- NIH/NIMHD grant [MD009124]
- NIH/NHLBI grant [K01HL103186]
- NSTIP strategic technologies program in the Kingdom of Saudi Arabia [10-BIO1253-03]
- NIH/NCI grant [P30CA016059]
The fundamental pathophysiology of sickle cell disease is predicated by the polymerization of deoxygenated (T-state) sickle hemoglobin (Hb S) into fibers that distort red blood cells into the characteristic sickle shape. The crystal structure of deoxygenated Hb S (DeoxyHb S) and other studies suggest that the polymer is initiated by a primary interaction between the mutation beta Val6 from one Hb S molecule, and a hydrophobic acceptor pocket formed by the residues beta Ala70, beta Phe85 and beta Leu88 of an adjacent located Hb S molecule. On the contrary, oxygenated or liganded Hb S does not polymerize or incorporate in the polymer. In this paper we present the crystal structure of carbonmonoxy-ligated sickle Hb (COHb S) in the quaternary classical R-state at 1.76 angstrom. The overall structure and the pathological donor and acceptor environments of COHb S are similar to those of the isomorphous CO-ligated R-state normal Hb (COHb A), but differ significantly from DeoxyHb S as expected. More importantly, the packing of COHb S molecules does not show the typical pathological interaction between beta Val6 and the beta Ala70, beta Phe85 and beta Leu88 hydrophobic acceptor pocket observed in DeoxyHb S crystal. The structural analysis of COHb S, COHb A and DeoxyHb S provides atomic level insight into why liganded hemoglobin does not form a polymer. (C) 2016 Elsevier Inc. All rights reserved.
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