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Victoria L. Wyckelsma Tomas Venckunas Peter J. Houweling Maja Schlittler Volker M. Lauschke Chrystal F. Tiong Harrison D. Wood Niklas Ivarsson Henrikas Paulauskas Nerijus Eimantas Daniel C. Andersson Kathryn N. North Marius Brazaitis Håkan Westerblad 《American journal of human genetics》2021,108(3):446-457
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《Journal of molecular biology》2021,433(24):167309
The NLRP3 inflammasome assembles in response to a variety of pathogenic and sterile danger signals, resulting in the production of interleukin-1β and interleukin-18. NLRP3 is a key component of the innate immune system and has been implicated as a driver of a number of acute and chronic diseases. We report the 2.8 Å crystal structure of the NLRP3 NACHT domain in complex with an inhibitor. The structure defines a binding pocket formed by the four subdomains of the NACHT domain, and shows the inhibitor acts as an intramolecular glue, which locks the protein in an inactive conformation. It provides further molecular insight into our understanding of NLRP3 activation, helps to detail the residues involved in subdomain coordination within the NLRP3 NACHT domain, and gives molecular insights into how gain-of-function mutations de-stabilize the inactive conformation of NLRP3. Finally, it suggests stabilizing the auto-inhibited form of the NACHT domain is an effective way to inhibit NLRP3, and will aid the structure-based development of NLRP3 inhibitors for a range of inflammatory diseases. 相似文献
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《Journal of molecular biology》2021,433(8):166838
Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate to generate a key lipid second messenger, phosphatidylinositol 3,4,5-bisphosphate. PI3Kα and PI3Kγ require activation by RAS proteins to stimulate signaling pathways that control cellular growth, differentiation, motility and survival. Intriguingly, RAS binding to PI3K isoforms likely differ, as RAS mutations have been identified that discriminate between PI3Kα and PI3Kγ, consistent with low sequence homology (23%) between their RAS binding domains (RBDs). As disruption of the RAS/PI3Kα interaction reduces tumor growth in mice with RAS- and epidermal growth factor receptor driven skin and lung cancers, compounds that interfere with this key interaction may prove useful as anti-cancer agents. However, a structure of PI3Kα bound to RAS is lacking, limiting drug discovery efforts. Expression of full-length PI3K isoforms in insect cells has resulted in low yield and variable activity, limiting biophysical and structural studies of RAS/PI3K interactions. This led us to generate the first RBDs from PI3Kα and PI3Kγ that can be expressed at high yield in bacteria and bind to RAS with similar affinity to full-length PI3K. We also solved a 2.31 Å X-ray crystal structure of the PI3Kα-RBD, which aligns well to full-length PI3Kα. Structural differences between the PI3Kα and PI3Kγ RBDs are consistent with differences in thermal stability and may underly differential RAS recognition and RAS-mediated PI3K activation. These high expression, functional PI3K RBDs will aid in interrogating RAS interactions and could aid in identifying inhibitors of this key interaction. 相似文献
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