NMR characterization of weak interactions between RhoGDI2 and fragment screening hits

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• 作者：Jiuyang Liu ; Jia Gao ; Fudong Li ; Rongsheng Ma ; Qingtao Wei ; Aidong Wang ; Jihui Wu ; Ke Ruan ; ^{kruan@ustc.edu.cn}
• 关键词：Fragment-based lead discovery ; Rho guanine-nucleotide dissociation inhibitor 2 ; Transferred paramagnetic relaxation enhancement ; Non-uniform sampling NMR ; Posttranslational modification
• 刊名：Biochimica et Biophysica Acta (BBA) - General Subjects
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：1861
• 期：1
• 页码：3061-3070
• 全文大小：1689 K
• 卷排序：1861

文摘

Unbound RhoGDI2 structure reveals a conserved geranylgeranyl binding pocket Small molecules targeting RhoGDI2 are identified using NMR fragment screening Integrated NMR approaches delineate weak interactions of RhoGDI2 and hits Mutagenesis and structure-affinity analysis validate the binding modeIn briefRhoGDI2 is a potential anti-metastasis target but lack any small molecule inhibitors. Liu et al. identify three RhoGDI2 hits using NMR fragment-based screening and delineate the weak interactions using chemical shift perturbations and transferred paramagnetic relaxation enhancement. The binding mode is cross-validated using site-directed mutagenesis and structure-affinity analysis.