THE HIGH-RESOLUTION CRYSTAL-STRUCTURE OF DEOXYHEMOGLOBIN-S

We have refined the crystal structure of deoxyhemoglobin S (beta Glu6 --> Val) at 2.05 Angstrom resolution to an R-factor of 16.5% (free A = 21.5%) using crystals isomorphous to those originally grown by Wishne r and Love. A predominant feature of this crystal form is a double str and of hemoglobin tetramers that has been shown by a variety of techni ques to be the fundamental building block of the intracellular sickle cell fiber. The double strand is stabilized by lateral contacts involv ing the mutant valine interacting with a pocket between the E and F he lices on another tetramer. The new structure reveals some marked diffe rences from the previously refined 3.0 Angstrom resolution structure, including several residues in the lateral contact which have shifted b y as much as 3.5 Angstrom. The lateral contact includes, in addition t o the hydrophobic interactions involving the mutant valine, hydrophili c interactions and bridging water molecules at the periphery of the co ntact. This structure provides further insights into hemoglobin polyme rization and may be useful for the structure-based design of therapeut ic agents to treat sickle cell disease. (C) 1997 Academic Press Limite d.