ATOMIC STRUCTURES OF THE HUMAN IMMUNOPHILIN FKBP-12 COMPLEXES WITH FK506 AND RAPAMYCIN
ATOMIC STRUCTURES OF THE HUMAN IMMUNOPHILIN FKBP-12 COMPLEXES WITH FK506 AND RAPAMYCIN
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DOI：
10.1006/jmbi.1993.1012
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发表时间：
1993-01-05
影响因子：
5.6
通讯作者：
CLARDY, J
中科院分区：
文献类型：
--
作者：
VANDUYNE, GD;STANDAERT, RF;CLARDY, J
免疫抑制剂FK 506和雷帕霉素与人亲免素FKBP-12形成的复合物的高分辨率结构已通过X射线衍射测定。FKBP-12有一个新的折叠，由一个五链β-折叠包裹在一个整体呈圆锥形的短α-螺旋周围。FK 506和雷帕霉素都结合在由β-折叠、α-螺旋和三个环限定的空腔中。FK 506和雷帕霉素都以类似的方式与一组氢键和一个不寻常的羰基结合口袋结合。结合的FK 506具有与游离（结晶）FK 506不同的构象，而雷帕霉素的结合构象与未结合的雷帕霉素的结合构象几乎相同。FKBP-12是一种肽基脯氨酰异构酶（PPIase），复合物的结构表明了这种催化活性可以发挥作用的方式。不同的复合物在抑制T细胞活化的不同步骤中具有活性，这种活性似乎与PPIase活性无关。
High resolution structures for the complexes formed by the immunosuppressive agents FK506 and rapamycin with the human immunophilin FKBP-12 have been determined by X-ray diffraction. FKBP-12 has a novel fold comprised of a five-stranded β-sheet wrapping around a short α-helix with an overall conical shape. Both FK506 and rapamycin bind in the cavity defined by the β-sheet, α-helix and three loops. Both FK506 and rapamycin bind in similar fashions with a set of hydrogen bonds and an unusual carbonyl binding pocket. Bound FK506 has different conformation than free (crystalline) FK506 while rapamycin's bound conformation is virtually identical to that of unbound rapamycin. FKBP-12 is a peptidyl-prolyl isomerase (PPIase), and the structures of the complexes suggest ways in which this catalytic activity could operate. The different complexes are active in suppressing different steps of T cell activation, an activity seemingly unconnected with the PPIase activity.