Structure of the fifth EGF-like domain of thrombomodulin: An EGF-like domain with a novel disulfide-bonding pattern
Structure of the fifth EGF-like domain of thrombomodulin: An EGF-like domain with a novel disulfide-bonding pattern
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DOI：
10.1006/jmbi.1997.1356
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发表时间：
1997-11-07
影响因子：
5.6
通讯作者：
Komives, EA
中科院分区：
文献类型：
--
作者：
Benitez, BAS;Hunter, MJ;Komives, EA
血栓调节蛋白（TMEGF 5）的第五个EGF样结构域（残基Q387至E426）的结构已通过二维NMR确定。TMEGF 5以1.9 μ M的Ki与凝血酶结合，并已显示在TM的完全活性片段中具有新的二硫键模式。在EGF中，二硫键模式是（1 - 3，2 - 4，5 - 6），而TMEGF 5具有非交叉（1 - 2，3 - 4，5 - 6）模式。从483个NOE衍生的距离限制确定的tl-Lis新结构域的结构似乎与常见的EGF样结构不同。TMEGF 5的14个最低能量结构的叠加给出了总体r.m.s.d.。1.09埃。TMEGF5中不存在所有EGF样结构域共有的中心双链β折叠。A环（残基C390至C395）与B环（残基C399至C407）的相互作用发生扭曲，如EGF中一样，并且靠近C环（残基C409至C421）。这种扭曲导致TMEGF5中的N和C末端比EGF中更靠近。大多数对活性重要的残基位于分子的一面，这可能是结构域的凝血酶结合表面。该结构域内C环的结构是类似于EGF的β-发夹，与转移NOE实验确定的与凝血酶结合的合成环的结构相似。尽管环的结构相似，但紧接在C421之后的残基在两种结构中处于不同位置，这表明这些"尾"残基在凝血酶结合时可能改变构象。(C)出版社：Academic Press Limited。
The structure of the fifth EGF-like domain (residues Q387 to E426) of thrombomodulin (TMEGF5) has been determined by two-dimensional NMR. TMEGF5 binds to thrombin with a K-i of 1.9 mu M and has been shown to have a novel disulfide bonding pattern in a fully active fragment of TM. In EGF, the disulfide bonding pattern is (1-3,2-4,5-6), while TMEGF5 has an uncrossed (1-2,3-4,5-6) pattern. The structure of tl-Lis novel domain, determined from 483 NOE-derived distance restraints, appears to have diverged from the common EGF-like structure. Superposition of the 14 lowest-energy structures of TMEGF5 gives an overall r.m.s.d. of 1.09 Angstrom for the backbone atoms. The central two-stranded beta-sheet common to all EGF-like domains is not present in TMEGF5. The A loop, residues C390 to C395, is twisted away from interacting with the B loop, residues C399 to C407, as in EGF, and is close to the C loop, residues C409 to C421. This twist causes the N and C termini to be closer together in TMEGF5 than in EGF. Most of the residues that are important for activity lie on one face of the molecule, which is likely to be the thrombin-binding surface of the domain. The structure of the C loop within the domain, which is a beta-hairpin similar to EGF, is similar to the structure of a synthetic version of the loop bound to thrombin as determined by transferred NOE experiments. Despite the similarity in the structures of the loops, the residues immediately following C421 are in different positions in the two structures suggesting that these ''tail'' residues may change conformation upon thrombin binding. (C) 1997 Academic Press Limited.