Location of voxelotor in sickle fiber. (A) The X-ray structure of voxelotor bound to the R conformation of Hb shows that the drug is located in a complementary pocket between α chains (green) of the structure (Protein Database; PDB 5E83),^56,57 and (B) when modeled using the same conformation as in R, it can easily fit into the pocket of the deoxyHbS structure (T conformation) (PDB 2HBS).⁵⁸ Hb is shown in a ribbon representation and drug in a magenta, space-filling representation. (C) The HbS fiber structure model is shown in a space-filling representation. It consists of 14 strands, which can be grouped into 7 twinned (doubled) strands⁵⁹ bridged by axial (D) and lateral (E) contacts, similar to those in the T crystal structure illustrated. The drug is located far from both the canonical axial and equatorial interfaces between Hb tetramers in the twinned strands. It is, however, closer to other possible contacts present in the fiber. Beta6 valine is the orange molecule in panels E and F. (F) The closest approach of the drug to a neighboring tetramer, in which the nearest heavy atom distance between drug and neighbor is still 7.6 Å. Thus, there appear to be no interfaces in the fiber where voxelotor would directly interfere with polymerization.