A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.
A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.
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DOI：
10.1021/bi201055c
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发表时间：
2011-11-08
期刊：
影响因子：
2.9
通讯作者：
Etzkorn, Felicia A.
中科院分区：
文献类型：
--
作者：
Xu, Guoyan G.;Zhang, Yan;Mercedes-Camacho, Ana Y.;Etzkorn, Felicia A.
研究了细胞周期调节肽基丙氨酸异构酶（PPIase, Pin1）的机制，使用设计的还原酰胺抑制剂来模拟扭曲酰胺过渡态。合成了Pin1抑制剂R - pser -Ψ [CH2N] - pro - 2-（吲哚-3-基）-乙胺，1 （R =氟酰甲氧羰基，Fmoc）和2 (R = Ac)，并进行了生物测定。抑制剂1的IC50值为6.3 μM，对Pin1的抑制效果是基态类似物（含顺式酰胺烯同异构体抑制剂）的4.5倍。在2中，将Fmoc转变为Ac，提高了溶液的溶解度，使IC50值达到12 μM。2与Pin1结合的配合物的x射线结构被确定为1.76 Å分辨率。结构表明，还原的酰胺采用了类似于Pin1的扭曲酰胺过渡态的构象，具有脯氨酸环的反式吡咯烷构象。类似的底物构象相对于平面酰胺构象是不稳定的。另外三种还原酰胺，Thr取代Ser， l-或d-pipecolate （Pip）取代Pro，是Pin1的稍弱抑制剂。
The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R–pSer–Ψ[CH2N]–Pro–2-(indol-3-yl)-ethylamine, 1 (R = fluorenylmethoxycarbonyl, Fmoc), and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC50 value of 6.3 μM, which is 4.5-fold better inhibition for Pin1 than our comparable ground state analogue, a cis-amide alkene isostere containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination, and resulted in an IC50 value of 12 μM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 Å resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser, and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
15
作者：
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通讯作者：
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影响因子：
16
作者：
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通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
THOMPSON, RM
影响因子：
64.5
作者：
Ranganathan, R;Lu, KP;Noel, JP
通讯作者：
Noel, JP