Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases
Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases
复制标题
DOI：
10.1042/bj20051931
复制
发表时间：
2006-05-01
影响因子：
4.1
通讯作者：
Barr, AJ
中科院分区：
文献类型：
--
作者：
Eswaran, J;Von Kries, JP;Barr, AJ
蛋白酪氨酸磷酸酶PTPN5、PTPRR和PTPN7组成了一个磷酸酶家族，可以特异性地灭活MAPKs（丝裂原活化蛋白激酶）。我们已经确定了所有人类家族成员的高分辨率结构，对24000个化合物进行筛选，并确定了两类抑制剂，环五[c]喹啉羧酸和2,5-二甲基吡咯基苯甲酸。比较结构分析揭示了这个保守家族的显著差异，可以探索选择性抑制剂的设计。PTPN5以两种不同的晶体形式结晶，其中硫酸盐离子靠近活性位点，而WPD（色氨酸- pro - asp）环具有独特的构象，在其他PTPs中没有见过，以3（10）螺旋结尾。在PTPN7结构中，WPD环呈封闭构象，可以看到部分KIM（激酶相互作用基序），它形成一个n端脂肪族螺旋，磷酸化位点Thr（66）位于可接近的位置。PTPRR的WPD环是开放的；然而，与其小鼠同源物PTPSL的结构相反，PTPSL在保守的赖氨酸和天冬氨酸残基之间存在一个盐桥，该盐桥被认为具有更严格的环结构，从而调节PTPSL的活性，而PTPRR中没有形成盐桥。其中一种已确定的抑制剂支架环penta[c]喹啉成功地对接到PTPRR中，这表明有几种可能的hit扩展。确定的结构与已建立的SAR（结构-活性关系）为开发选择性抑制剂提供了新的途径，这些抑制剂可能具有治疗PTPRR或靶向PTPN7的急性髓母细胞白血病的神经退行性疾病的治疗潜力。
Protein tyrosine phosphatases PTPN5, PTPRR and PTPN7 comprise a family of phosphatases that specifically inactivate MAPKs (mitogen-activated protein kinases). We have determined high-resolution structures of all of the human family members, screened them against a library of 24000 compounds and identified two classes of inhibitors, cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids. Comparative structural analysis revealed significant differences within this conserved family that could be explored for the design of selective inhibitors. PTPN5 crystallized, in two distinct crystal forms, with a sulphate ion in close proximity to the active site and the WPD (Trp-Pro-Asp) loop in a unique conformation, not seen in other PTPs, ending in a 3(10)-helix. In the PTPN7 structure, the WPD loop was in the closed conformation and part of the KIM (kinase-interaction motif) was visible, which forms an N-terminal aliphatic helix with the phosphorylation site Thr(66) in an accessible position. The WPD loop of PTPRR was open; however, in contrast with the structure of its mouse homologue, PTPSL, a salt bridge between the conserved lysine and aspartate residues, which has been postulated to confer a more rigid loop structure, thereby modulating activity in PTPSL, does not form in PTPRR. One of the identified inhibitor scaffolds, cyclopenta[c]quinoline, was docked successfully into PTPRR, suggesting several possibilities for hit expansion. The determined structures to-ether with the established SAR (structure-activity relationship) propose new avenues for the development of selective inhibitors that may have therapeutic potential for treating neurodegenerative diseases in the case of PTPRR or acute myeloblastic leukaemia targeting PTPN7.