LaLonde J M, Zhao B, Janson C A, D'Alessio K J, McQueney M S, Orsini M J, Debouck C M, Smith W W
Department of Structural Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Biochemistry. 1999 Jan 19;38(3):862-9. doi: 10.1021/bi9822271.
Cathepsin K is a cysteine protease present in human osteoclasts that plays an important role in bone resorption. Cathepsin K is synthesized as an inactive proenzyme and activated under conditions of low pH. Autoproteolytic processing of the N-terminal 99 amino acid propeptide produces the active, mature form of cathepsin K. It is presumed that the activation of procathepsin K in vivo occurs in the bone resorption pit, which has a low-pH environment. We have determined the structure of human procathepsin K at 2.8 A resolution. The structure of the mature enzyme domain within procathepsin K is virtually identical to that of mature cathepsin K. The fold of the propeptide of procathepsin K is similar to that observed in procathepsins B and L despite differences in length and sequence. A portion of the propeptide occupies the active site cleft of cathepsin K. Hydrophobic interactions, salt bridges, and hydrogen-bonding interactions are observed in the structure of the propeptide and between the propeptide and the mature enzyme of procathepsin K. These interactions suggest an explanation for the stability of the proenzyme. The structure of procathepsin K contributes to an understanding of the molecular basis of inhibition by the propeptide portion of the molecule and activation of this important member of the cysteine protease family.
组织蛋白酶K是一种存在于人类破骨细胞中的半胱氨酸蛋白酶，在骨吸收中起重要作用。组织蛋白酶K最初以无活性的酶原形式合成，并在低pH条件下被激活。对N端99个氨基酸的前肽进行自身催化加工后产生有活性的成熟形式的组织蛋白酶K。据推测，组织蛋白酶K原在体内的激活发生在具有低pH环境的骨吸收凹陷处。我们已经确定了人类组织蛋白酶K原在2.8埃分辨率下的结构。组织蛋白酶K原中成熟酶结构域的结构与成熟组织蛋白酶K的结构几乎相同。尽管长度和序列存在差异，但组织蛋白酶K原的前肽折叠与组织蛋白酶B和L原中观察到的折叠相似。前肽的一部分占据了组织蛋白酶K的活性位点裂隙。在前肽的结构以及组织蛋白酶K原的前肽与成熟酶之间观察到疏水相互作用、盐桥和氢键相互作用。这些相互作用为酶原的稳定性提供了解释。组织蛋白酶K原的结构有助于理解该分子前肽部分的抑制作用以及半胱氨酸蛋白酶家族这一重要成员的激活的分子基础。
