XFEL and NMR Structures of Francisella Lipoprotein Reveal Conformational Space of Drug Target against Tularemia.
XFEL and NMR Structures of Francisella Lipoprotein Reveal Conformational Space of Drug Target against Tularemia.
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DOI：
10.1016/j.str.2020.02.005
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发表时间：
2020-05-05
期刊：
影响因子：
5.7
通讯作者：
Fromme, Petra
中科院分区：
文献类型：
--
作者：
Zook, James;Shekhar, Mrinal;Hansen, Debra;Conrad, Chelsie;Grant, Thomas;Gupta, Chitrak;White, Thomas;Barty, Anton;Basu, Shibom;Zhao, Yun;Zatsepin, Nadia;Ishchenko, Andrii;Batyuk, Alex;Gati, Cornelius;Li, Chufeng;Galli, Lorenzo;Coe, Jesse;Hunter, Mark;Liang, Meng;Weierstall, Uwe;Nelson, Garret;James, Daniel;Stauch, Benjamin;Craciunescu, Felicia;Thifault, Darren;Liu, Wei;Cherezov, Vadim;Singharoy, Abhishek;Fromme, Petra
土拉热弗朗西斯菌是潜在致命性疾病土拉菌病的病原体。脂蛋白Flpp3已被鉴定为兔热病的毒力决定因子，在弗朗西斯属之外没有序列同源性。我们报告了Flpp3的室温结构，通过连续飞秒晶体学确定，其存在于与先前通过NMR确定的结构所描述的显著不同的构象中。此外，我们研究了这两种结构之间的构象空间和能量障碍的分子动力学伞形采样，并确定了三个低能量的中间状态，在室温下容易发生之间的转换。我们还开始研究可能作为Flpp3抑制剂的有机化合物。这项工作为开发针对兔热病的靶向治疗方法铺平了道路，并有助于我们了解兔热病的疾病机制。利用X射线自由电子激光（XFEL）技术，Zook等人描述了毒力决定簇Flpp 3的另一种蛋白质构象，并利用分子动力学（MD）研究了这些构象之间的构象景观。MD鉴定了几种中间构象，这些中间构象允许这些构象转变在生理相关温度下发生，并为潜在致命疾病兔热病的潜在未来药物治疗提供了见解。
Francisella tularensis is the causative agent for the potentially fatal disease tularemia. The lipoprotein Flpp3 has been identified as a virulence determinant of tularemia with no sequence homology outside the Francisella genus. We report a room temperature structure of Flpp3 determined by serial femtosecond crystallography that exists in a significantly different conformation than previously described by the NMR-determined structure. Furthermore, we investigated the conformational space and energy barriers between these two structures by molecular dynamics umbrella sampling and identified three low-energy intermediate states, transitions between which readily occur at room temperature. We have also begun to investigate organic compounds in silico that may act as inhibitors to Flpp3. This work paves the road to developing targeted therapeutics against tularemia and aides in our understanding of the disease mechanisms of tularemia. Using X-ray free-electron laser (XFEL) technology, Zook et al. describe an alternative protein conformation of the virulence determinant Flpp3 and use molecular dynamics (MD) to investigate conformational landscapes between these conformations. MD identifies several intermediate conformations that allow these conformational transitions to occur at physiologically relevant temperatures and provide insight to potential future drug therapies for the potentially deadly disease tularemia.
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影响因子：
1.3
作者：
Koerner, L. J.;Philipp, H. T.;Gruner, S. M.
通讯作者：
Gruner, S. M.
DOI：
10.1007/s10969-011-9100-8
发表时间：
2011-07-01
期刊：
Journal of Structural and Functional Genomics
影响因子：
--
作者：
Cormier, Catherine Y.;Park, Jin G.;LaBaer, Joshua
通讯作者：
LaBaer, Joshua
影响因子：
5.7
作者：
Brock, Susan R.;Parmely, Michael J.
通讯作者：
Parmely, Michael J.
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：
6.1
作者：
Barty A;Kirian RA;Maia FR;Hantke M;Yoon CH;White TA;Chapman H
通讯作者：
Chapman H