Harrington D J, Adachi K, Royer W E
Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
J Mol Biol. 1997 Sep 26;272(3):398-407. doi: 10.1006/jmbi.1997.1253.
We have refined the crystal structure of deoxyhemoglobin S (beta Glu6-->Val) at 2.05 A resolution to an R-factor of 16.5% (free R=21. 5%) using crystals isomorphous to those originally grown by Wishner and Love. A predominant feature of this crystal form is a double strand of hemoglobin tetramers that has been shown by a variety of techniques to be the fundamental building block of the intracellular sickle cell fiber. The double strand is stabilized by lateral contacts involving the mutant valine interacting with a pocket between the E and F helices on another tetramer. The new structure reveals some marked differences from the previously refined 3.0 A resolution structure, including several residues in the lateral contact which have shifted by as much as 3.5 A. The lateral contact includes, in addition to the hydrophobic interactions involving the mutant valine, hydrophilic interactions and bridging water molecules at the periphery of the contact. This structure provides further insights into hemoglobin polymerization and may be useful for the structure-based design of therapeutic agents to treat sickle cell disease.
我们使用与Wishner和Love最初培养的晶体同晶型的晶体，将脱氧血红蛋白S（βGlu6→Val）的晶体结构精修至2.05 Å分辨率，R因子为16.5%（自由R = 21.5%）。这种晶体形式的一个主要特征是血红蛋白四聚体的双链，通过多种技术已证明其是细胞内镰状细胞纤维的基本构建单元。双链通过横向接触得以稳定，其中突变缬氨酸与另一个四聚体上E和F螺旋之间的一个口袋相互作用。新结构揭示了与之前精修的3.0 Å分辨率结构的一些显著差异，包括横向接触中的几个残基移动了多达3.5 Å。除了涉及突变缬氨酸的疏水相互作用外，横向接触还包括亲水相互作用以及接触周边的桥连水分子。该结构为血红蛋白聚合提供了进一步的见解，可能有助于基于结构设计治疗镰状细胞病的药物。
