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. 2016 Jun;194(3):446-50.
doi: 10.1016/j.jsb.2016.04.003. Epub 2016 Apr 13.

Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation

Mohini S Ghatge  1 , Mostafa H Ahmed  1 , Abdel Sattar M Omar  2 , Piyusha P Pagare  1 , Susan Rosef  3 , Glen E Kellogg  1 , Osheiza Abdulmalik  4 , Martin K Safo  5
Affiliations

Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation

Mohini S Ghatge et al. J Struct Biol. 2016 Jun.

Abstract

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 βVal6 from one Hb S molecule, and a hydrophobic acceptor pocket formed by the residues βAla70, βPhe85 and βLeu88 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 1.76Å. 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 βVal6 and the βAla70, βPhe85 and βLeu88 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.

Keywords: Allosteric; Crystal structure; Hemoglobin; Mutation; R-state; Sickle cell disease.

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Figures

Fig. 1
Fig. 1. Structure of DeoxyHb S (PDB code 2HBS)
(A) Ribbon figure of the crystal packing of deoxyHb S. (B) The pathological β2Val6 in one strand (blue) interacts with a hydrophobic pocket formed by β1Ala70, β1Phe85, and β1Leu88 from the β1 subunit of a heterotetramer positioned in the adjacent polymeric strand (green). This interaction is stabilized by a hydrogen-bond contact between β2Thr4 and β1Asp73.
Fig. 2
Fig. 2. Crystal structure of COHb S
(A) Stereo-view of the initial electron density (2Fo-Fc) map with alanine at the 6th position of the β-subunit during the refinement, contoured at 1.0σ. (B) Stereo-view of the final 2Fo-Fc map with valine at the 6th position of the β-subunit during the refinement, contoured at 1.0σ. The two maps are superimposed with the final refined model.
Fig. 2
Fig. 2. Crystal structure of COHb S
(A) Stereo-view of the initial electron density (2Fo-Fc) map with alanine at the 6th position of the β-subunit during the refinement, contoured at 1.0σ. (B) Stereo-view of the final 2Fo-Fc map with valine at the 6th position of the β-subunit during the refinement, contoured at 1.0σ. The two maps are superimposed with the final refined model.
Fig. 3
Fig. 3. Structure analysis of COHb S and DeoxyHb S
(A) Ribbon figure of the crystal packing of COHb S. (B) The β-subunit A helix (with βVal6 and βThr4) of COHb S (yellow) and DeoxyHb S (blue) after superposing the β2-subunits (3-138 residues) of the two structures. (C) The hydrophobic acceptor pocket formed by βAla70, βPhe85, and βLeu88 of COHb S (yellow) and DeoxyHb S (blue) after superposing the β1-subunits (3-138 residues) of the two structures.
See this image and copyright information in PMC

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