期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1991
卷号：88
期号：6
页码：2209-2211
DOI：10.1073/pnas.88.6.2209
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The hemoglobin binding site of the antisickling agent 12C79 has been determined by x-ray crystallography. 12C79 is recognized as one of the first molecules to reach clinical trials that was designed, de novo, from x-ray-determined atomic coordinates of a protein. Several previous attempts to verify the proposed Hb binding sites via crystallographic studies have failed. Using revised experimental procedures, we obtained 12C79-deoxyhemoglobin crystals grown after reaction with oxyhemoglobin and cyanoborohydride reduction to stabilize the Schiff base linkage. The difference electron-density Fourier maps show that two 12C79 molecules bind covalently to both symmetry-related N-terminal amino groups of the hemoglobin alpha chains. This is in contrast to the original design that proposed the binding of one drug molecule that spans the molecular dyad to interact with both N-terminal alpha-amino groups.
