Structural basis for the functional differences between type I and type II human methionine aminopeptidases
Structural basis for the functional differences between type I and type II human methionine aminopeptidases
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DOI：
10.1021/bi051691k
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发表时间：
2005-11-15
期刊：
影响因子：
2.9
通讯作者：
Matthews, BW
中科院分区：
文献类型：
--
作者：
Addlagatta, A;Hu, XY;Matthews, BW
人类MetAP1晶体结构的测定首次使比较同一生物体的I型和II型蛋氨酸氨基肽酶(Metap)的结构成为可能。将I型酶与先前报道的卵清蛋白与II型Metap的络合物进行比较，发现前者的活性部位变小，并与结合的抑制剂发生空间位阻冲突。这就解释了为什么卵黄素和相关的抗血管生成抑制剂针对的是II型人Metap而不是I型人Metap。MetAP1和MetAP2在活性部位的大小和形状上的差异也有助于解释它们不同的底物特异性。在过量的Co2+存在下，第三个钴离子结合在活性部位区域，这解释了为什么过量的金属离子可以抑制。此外，该蛋白的N-末端区域包含三个不同的Pro-x-x-Pro基序，支持先前的假设，即该蛋白质区域可能参与与核糖角的结合。
Determination of the crystal structure of human MetAP1 makes it possible, for the first time, to compare the structures of a Type I and a Type II methionine aminopeptidase (MetAP) from the same organism. Comparison of the Type I enzyme with the previously reported complex of ovalicin with Type II MetAP shows that the active site of the former is reduced in size and would incur steric clashes with the bound inhibitor. This explains why ovalicin and related anti-angiogenesis inhibitors target Type II human MetAP but not Type I. The differences in both size and shape of the active sites between MetAP1 and MetAP2 also help to explain their different substrate specificity. In the presence of excess Co2+, a third cobalt ion binds in the active site region, explaining why metal ions in excess can be inhibitory. Also, the N-terminal region of the protein contains three distinct Pro-x-x-Pro motifs, supporting the prior suggestion that this region of the protein may participate in binding to the ribosorne.