The X-ray Crystal Structure of Full-length Human Plasminogen

Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand-binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change.

This entry contains two diffraction datasets:

G1-10 Glycoform 1 Humanplasminogen (PDB ID: 4DUU)
Xtal19 Glycoform2 Humanplasminogen (PDB ID: 4DUR)

Publication in Cell Reports 1(3) 185-190

纤溶酶原（plasminogen）是主要纤溶蛋白酶纤溶酶的酶原前体。循环中的纤溶酶原包含一个Pan-apple（PAp）结构域、五个kringle结构域（KR1-KR5）以及一个丝氨酸蛋白酶（serine protease, SP）结构域，呈现出封闭的抗激活构象。这些kringle结构域可介导与纤维蛋白凝块及细胞表面受体的相互作用。此类相互作用可触发纤溶酶原转变为可被激活的开放构象，进而可被组织型纤溶酶原激活剂及尿激酶型纤溶酶原激活剂切割并转化为纤溶酶。本研究中，封闭态纤溶酶原的结构显示，PAp结构域与SP结构域辅以氯离子，可通过与kringle阵列的相互作用维持其封闭构象。糖基化差异会改变KR3的位置，但所有结构中，被纤溶酶原激活剂识别切割的环结构均处于不可接触状态。KR1的配体结合位点处于暴露状态，大概率负责介导酶原向靶点的招募。此外，对本研究结构的分析表明，KR5脱离PAp结构域的过程或许是纤溶酶原构象改变的起始步骤。

本条目包含两组衍射数据集：
G1-10 糖型1人纤溶酶原（PDB编号：4DUU）
Xtal19 糖型2人纤溶酶原（PDB编号：4DUR）

本研究成果发表于《Cell Reports》第1卷第3期，页码185-190。