Zhang M, Stauffacher C V, Lin D, Van Etten R L
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, USA.
J Biol Chem. 1998 Aug 21;273(34):21714-20. doi: 10.1074/jbc.273.34.21714.
The low molecular weight phosphotyrosine phosphatases (PTPases) constitute a distinctive class of phosphotyrosine phosphatases that is widely distributed among vertebrate and invertebrate organisms. In vertebrates, two isoenzymes of these low molecular weight PTPases are commonly expressed. The two human isoenzymes, HCPTPA and HCPTPB, differ in an alternatively spliced sequence (residues 40-73) referred to as the variable loop, resulting in isoenzymes that have different substrate specificities and inhibitor/activator responses. We present here the x-ray crystallographic structure of a human low molecular weight PTPase solved by molecular replacement to 2.2 A. The structure of human low molecular weight PTPase is compared with a structure representing the other isoenzyme in this PTPase class, in each case with a sulfonate inhibitor bound to the active site. Possible aromatic residue interactions with the phosphotyrosine substrate are proposed from an examination of the binding site of the inhibitors. Differences are observed in the variable loop region, which forms one wall and the floor of a long crevice leading from the active-site loop. A set of residues lying along this crevice (amino acids 49, 50, and 53) is suggested to be responsible for differences in substrate specificity in these two enzymes.
低分子量磷酸酪氨酸磷酸酶（PTPases）构成了一类独特的磷酸酪氨酸磷酸酶，广泛分布于脊椎动物和无脊椎动物中。在脊椎动物中，通常表达这些低分子量PTPases的两种同工酶。两种人类同工酶，HCPTPA和HCPTPB，在一个被称为可变环的选择性剪接序列（残基40 - 73）上有所不同，导致同工酶具有不同的底物特异性以及抑制剂/激活剂反应。我们在此展示了通过分子置换解析到2.2埃分辨率的人类低分子量PTPase的X射线晶体结构。将人类低分子量PTPase的结构与该PTPase类中代表另一种同工酶的结构进行了比较，每种情况均有一个磺酸盐抑制剂结合到活性位点。通过检查抑制剂的结合位点，提出了与磷酸酪氨酸底物可能的芳香族残基相互作用。在可变环区域观察到差异，该区域形成了一条从活性位点环引出的长裂缝的一侧壁和底部。沿着这条裂缝排列的一组残基（氨基酸49、50和53）被认为是这两种酶底物特异性差异的原因。
