Crystal structure of deoxy-human hemoglobin beta 6 Glu -> Trp - Implications for the structure and formation of the sickle cell fiber

An atomic-level understanding of the interactions between hemoglobin molecu les that contribute to the formation of pathological fibers in sickle cell disease remains elusive. By exploring crystal structures of mutant hemoglob ins with altered polymerization properties, insight can be gained into sick le cell hemoglobin (HbS) polymerization. We present here the 2.0-Angstrom r esolution deoxy crystal structure of human hemoglobin mutated to tryptophan at the beta 6 position, the site of the glutamate --> valine mutation in H bS. Unlike leucine and isoleucine, which promote polymerization relative to RbS, tryptophan inhibits polymerization. Our results provide explanations for the altered polymerization properties and reveal a fundamentally differ ent double strand that may provide a model for interactions within a fiber and/or interactions leading to heterogeneous nucleation.