Crystal structure of prolyl 4-hydroxylase from Bacillus anthracis.
Crystal structure of prolyl 4-hydroxylase from Bacillus anthracis.
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DOI：
10.1021/bi901771z
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发表时间：
2010-01-12
期刊：
影响因子：
2.9
通讯作者：
Limburg, Julian
中科院分区：
文献类型：
--
作者：
Culpepper, Megen A.;Scott, Emily E.;Limburg, Julian
脯氨酰4-羟化酶（P4 H）催化脯氨酸残基的翻译后羟基化，并在胶原蛋白的产生、缺氧反应和细胞壁发育中发挥作用。P4 H属于Fe（II）/αKG加氧酶，需要Fe（II）、α-酮戊二酸（αKG）和O2来维持活性。我们报道了炭疽杆菌的P4 H的1.40 bp结构，炭疽杆菌是炭疽的病原体，其免疫显性外孢壁蛋白BclA含有胶原样重复序列。结构揭示了Fe（II）/αKG加氧酶的双链β-螺旋核心折叠特征。该折叠将Fe-结合和α KG-结合残基定位在预期具有催化活性的方向，并且与活性位点口处的脯氨酸肽底物结合一致。炭疽-P4 H结构与Cr-P4 H-1结构的比较揭示了肽表面沟的相似性。然而，序列和结构比较表明，相邻环的构象差异可能会改变与肽底物的相互作用。这些差异可能是Cr-P4 H-1与炭疽和人P4 H酶的KM值之间的实质性差异的基础。此外，虽然P4 H酶的先前结构是单体，但炭疽芽孢杆菌P4 H形成α2同源二聚体，并表明残基对α2β2人胶原蛋白P4 H的α2亚基之间的相互作用很重要。因此，炭疽-P4 H结构提供了对人-P4 H α亚基的结构和功能的深入了解，这可能有助于开发参与纤维化疾病的人-P4 H酶的选择性抑制剂。
Prolyl 4-hydroxylases (P4H) catalyze the posttranslational hydroxylation of proline residues and play a role in collagen production, hypoxia response, and cell wall development. P4Hs belong to the Fe(II)/αKG oxygenases and require Fe(II), α-ketoglutarate (αKG), and O2 for activity. We report the 1.40 Å structure of a P4H from Bacillus anthracis, the causative agent of anthrax, whose immunodominant exosporium protein BclA contains collagen-like repeat sequences. The structure reveals the double stranded β-helix core fold characteristic of Fe(II)/αKG oxygenases. This fold positions Fe-binding and αKG-binding residues in what is expected to be catalytically-competent orientations and is consistent with proline peptide substrate binding at the active site mouth. Comparisons of the anthrax-P4H structure with Cr-P4H-1 structures reveal similarities in a peptide surface groove. However, sequence and structural comparisons suggest differences in conformation of adjacent loops may change the interaction with peptide substrates. These differences may be the basis of substantial disparity between the KM values for the Cr-P4H-1 vs. the anthrax and human P4H enzymes. Additionally, while previous structures of P4H enzymes are monomers, Bacillus anthracis P4H forms an α2 homodimer and suggests residues important for interactions between the α2 subunits of the α2β2 human collagen P4H. Thus the anthrax-P4H structure provides insight into the structure and function of the α subunit of human-P4H, which may aid in the development of selective inhibitors of the human-P4H enzyme involved in fibrotic disease.
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DOI：
10.1107/s090744499900846x
发表时间：
1999-10-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Leslie, AGW
通讯作者：
Leslie, AGW
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
影响因子：
56.9
作者：
HENDRICKSON, WA
通讯作者：
HENDRICKSON, WA
影响因子：
11.6
作者：
Keskiaho, Katriina;Hieta, Reija;Myllyharju, Johanna
通讯作者：
Myllyharju, Johanna
影响因子：
4.8
作者：
McDonough, MA;Kavanagh, KL;Schofield, CJ
通讯作者：
Schofield, CJ