Molecular basis of thrombomodulin activation of slow thrombin.
Molecular basis of thrombomodulin activation of slow thrombin.
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慢速凝血酶的血栓调节蛋白激活的分子基础。
DOI：
10.1111/j.1538-7836.2009.03563.x
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Huntington JA
中科院分区：
文献类型：
--
作者：
Adams TE;Li W;Huntington JA
Coagulation is a highly regulated process where the ability to prevent blood loss after injury is balanced against the maintenance of blood fluidity. Thrombin is at the center of this balancing act. It is the critical enzyme for producing and stabilizing a clot, but when complexed with thrombomodulin (TM) it is converted to a powerful anticoagulant. Another cofactor that may play a role in determining thrombin function is the monovalent cation Na+. Its apparent affinity suggests that half of the thrombin generated is in a Na+-free ‘slow’ state and half is in a Na+-coordinated ‘fast’ state. While slow thrombin is a poor procoagulant enzyme, when complexed to TM it is an effective anticoagulant. To better understand this molecular transformation we solved a 2.4 Å structure of thrombin complexed with EGF domains 4–6 of TM in the absence of Na+ and other cofactors or inhibitors. We find that TM binds as previously observed, and that the thrombin component resembles structures of the fast form. The Na+ binding loop is observed in a conformation identical to the Na+-bound form, with conserved water molecules compensating for the missing ion. Using the fluorescent probe p-aminobenzamidine we show that activation of slow thrombin by TM principally involves the opening of the primary specificity pocket. These data show that TM binding alters the conformation of thrombin in a similar manner as Na+ coordination, resulting in an ordering of the Na+ binding loop and an opening of the adjacent S1 pocket. We conclude that other, more subtle subsite changes are unlikely to influence thrombin specificity toward macromolecular substrates.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
46.9
作者：
Dang, QD;Guinto, ER;DiCera, E
通讯作者：
DiCera, E
影响因子：
5.7
作者：
Huntington, JA;Esmon, CT
通讯作者：
Esmon, CT
DOI：
10.1016/0006-291x(90)90350-v
发表时间：
1990-06-15
影响因子：
3.1
作者：
HORTIN, GL;BENUTTO, BM
通讯作者：
BENUTTO, BM