The Crystal Structure of Cysteamine Dioxygenase Reveals the Origin of the Large Substrate Scope of This Vital Mammalian Enzyme.
The Crystal Structure of Cysteamine Dioxygenase Reveals the Origin of the Large Substrate Scope of This Vital Mammalian Enzyme.
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DOI：
10.1021/acs.biochem.1c00463
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发表时间：
2021-12-07
期刊：
影响因子：
2.9
通讯作者：
Brunold TC
中科院分区：
文献类型：
--
作者：
Fernandez RL;Elmendorf LD;Smith RW;Bingman CA;Fox BG;Brunold TC
我们报道了哺乳动物非血红素铁酶半胱胺双加氧酶（ADO）在1.9 Å分辨率下的第一个晶体结构，该结构显示铁和3-组氨酸（3-His）活性位点位于宽底物进入通道的末端。对活性位点的开放途径与最近的发现一致，ADO不仅催化半胱胺转化为次牛磺酸，而且还催化n -末端半胱氨酸（Nt-Cys）肽氧化为相应的亚磺酸，作为真核N-degron途径的一部分。利用分子动力学和量子力学/分子力学计算生成的ADO与半胱胺或Nt-Cys肽复合物的全蛋白模型表明，肽底物结合阻断了进入活性位点的途径。这一发现强调了从酶的反面通向活性位点的小通道的重要性，这为共底物O2进入铁中心提供了一条途径。有趣的是，这个通道的入口由两个Cys残基守卫，它们可能形成二硫键，以响应细胞内氧化还原电位的变化来调节O2输送。值得注意的是，在人ADO中能够形成交联的Cys和酪氨酸（Tyr）残基位于铁中心~7 Å处。因此，在ADO中，交联形成可能在结构或功能上并不重要。
We report the first crystal structure of the mammalian non-heme iron enzyme cysteamine dioxygenase (ADO) at 1.9 Å resolution, which shows an Fe- and 3-histidine (3-His) active site situated at the end of a wide substrate access channel. The open approach to the active site is consistent with the recent discovery that ADO catalyzes not only the conversion of cysteamine to hypotaurine, but also the oxidation of N-terminal cysteine (Nt-Cys) peptides to their corresponding sulfinic acids as part of the eukaryotic N-degron pathway. Whole-protein models of ADO in complex with either cysteamine or an Nt-Cys peptide, generated using molecular dynamics and quantum mechanics/molecular mechanics calculations, suggest occlusion of access to the active site by peptide substrate binding. This finding highlights the importance of a small tunnel that leads from the opposite face of the enzyme into the active site, providing a path through which co-substrate O2 could access the Fe center. Intriguingly, the entrance to this tunnel is guarded by two Cys residues that may form a disulfide bond to regulate O2 delivery in response to changes in the intracellular redox potential. Notably, the Cys and tyrosine (Tyr) residues shown to be capable of forming a cross-link in human ADO reside ~7 Å from the iron center. As such, cross-link formation may not be structurally or functionally significant in ADO.
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DOI：
10.1016/j.bbapap.2015.04.015
发表时间：
2015-08
影响因子：
3.2
作者：
Gerlt, John A.;Bouvier, Jason T.;Davidson, Daniel B.;Imker, Heidi J.;Sadkhin, Boris;Slater, David R.;Whalen, Katie L.
通讯作者：
Whalen, Katie L.
DOI：
10.1007/s00775-021-01904-5
发表时间：
2021-12
期刊：
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
影响因子：
--
作者：
Fernandez RL;Juntunen ND;Fox BG;Brunold TC
通讯作者：
Brunold TC
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
4.4
作者：
SCHAFER, A;HUBER, C;AHLRICHS, R
通讯作者：
AHLRICHS, R