García-Castellanos Raquel, Tallant Cynthia, Marrero Aniebrys, Solà Maria, Baumann Ulrich, Gomis-Rüth F Xavier
Departament de Biologia Estructural, Institut de Biologia Molecular de Barcelona, CSIC, c/Jordi Girona, 18-26, E-08034 Barcelona, Spain.
Arch Biochem Biophys. 2007 Jan 1;457(1):57-72. doi: 10.1016/j.abb.2006.10.004. Epub 2006 Oct 24.
Human pappalysin-1 is a multi-domain metalloprotease engaged in the homeostasis of insulin-like growth factors and the founding member of the pappalysin family within the metzincin clan of metalloproteases. We have recently identified an archaeal relative, ulilysin, encompassing only the protease domain. It is a 262-residue active protease with a novel 3D structure with two subdomains separated by an active-site cleft. Despite negligible overall sequence similarity, noticeable similarity is found with other metzincin prototypes, adamalysins/ADAMs and matrix metalloproteinases. Ulilysin has been crystallised in a product complex with an arginine-valine dipeptide occupying the active-site S(1') and S(2') positions and in a complex with the broad-spectrum hydroxamic acid-based metalloprotease inhibitor, batimastat. This molecule inhibits mature ulilysin with an IC(50) value of 61 microM under the conditions assayed. The binding of batimastat to ulilysin evokes binding to vertebrate matrix metalloproteases but is much weaker. These data give insight into substrate specificity and mechanism of action and inhibition of the novel pappalysin family.
人妊娠相关血浆蛋白 A1 是一种多结构域金属蛋白酶，参与胰岛素样生长因子的稳态调节，是金属蛋白酶M12家族中妊娠相关血浆蛋白家族的创始成员。我们最近鉴定出一种古菌相关蛋白，uli溶素，它仅包含蛋白酶结构域。它是一种由262个残基组成的活性蛋白酶，具有新颖的三维结构，有两个由活性位点裂隙分隔的亚结构域。尽管总体序列相似性可忽略不计，但与其他M12家族原型、解整合素金属蛋白酶/ADAMs和基质金属蛋白酶存在明显相似性。uli溶素已与占据活性位点S(1')和S(2')位置的精氨酸 - 缬氨酸二肽形成产物复合物结晶，并与基于异羟肟酸的广谱金属蛋白酶抑制剂batimastat形成复合物结晶。在测定条件下，该分子以61微摩尔的IC(50)值抑制成熟的uli溶素。batimastat与uli溶素的结合引发了与脊椎动物基质金属蛋白酶的结合，但较弱。这些数据为新型妊娠相关血浆蛋白家族的底物特异性、作用机制和抑制作用提供了深入了解。
