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Kim, Kuglae,Cha, Jeong Seok,Cho, Yong-Soon,Kim, Hoyoung,Chang, Nienping,Kim, Hye-Jung,Cho, Hyun-Soo Elsevier 2018 Journal of molecular biology Vol.430 No.10
<P><B>Abstract</B></P> <P>Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Structure of DYRK3 unveils three auto-phosphorylation sites. </LI> <LI> NAPA domain stabilizes N-lobe domain of DYRK3. </LI> <LI> Phosphorylation sites of PRAS40 by DYRK3 are identified. </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim Hoyoung,Lim Taehyun,Ha Go Eun,Lee Jee-Young,Kim Jun-Woo,Chang Nienping,Kim Si Hyun,Kim Ki Hun,Lee Jaeick,Cho Yongju,Kim Byeong Wook,Abrahamsson Alva,Kim Sung Hwan,Kim Hyo-Ji,Park Sehan,Lee Sang Ja 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists—BMK-C203 and BMK-C205—and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.