Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype.
Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype.
复制标题
DOI：
10.1007/s10822-011-9469-2
复制
发表时间：
2011-09
影响因子：
3.5
通讯作者：
Schürer SC
中科院分区：
文献类型：
--
作者：
Vidović D;Xie Y;Rinderspacher A;Deng SX;Landry DW;Chung C;Smith DH;Tautz L;Schürer SC
The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites.
登录
查看更多内容
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
9.8
作者：
Kyogoku, C;Langefeld, CD;Behrens, TW
通讯作者：
Behrens, TW
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL
影响因子：
64.5
作者：
Barr AJ;Ugochukwu E;Lee WH;King ON;Filippakopoulos P;Alfano I;Savitsky P;Burgess-Brown NA;Müller S;Knapp S
通讯作者：
Knapp S
影响因子：
56.9
作者：
JIA, ZC;BARFORD, D;TONKS, NK
通讯作者：
TONKS, NK