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    Receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been recently proposed as a potential target for cancer treatment. It was suggested that monoclonal antibodies (mAb) against the Kringle (KNG) domain of ROR1 could induce apoptosis of chronic lymphocytic leukemia cells. Here, we reported the determination of the solution structure of human ROR1-KNG (hROR1-KNG), investigation of its dynamic properties and potential binding interface by NMR spectroscopy. The obtained NMR structure of hROR1-KNG exhibits an open form at Asn47-His50 and shows obvious differences from other canonical KNGs at the corresponding lysine binding site, which implies that hROR1-KNG may interact with some non-canonical ligands. Dynamics analysis of hROR1-KNG reveal a faster local motion around the α-turn and 310-helix, which may provide flexibility to protect the proximal hydrophobic core in solution or facilitate the binding of other molecules. The intermediate-to-slow conformational exchange of Cys77-Ile79 may influence the conformation determination of disulfide bond Cys53-Cys77. Binding interface of hROR1-KNG for mAb R11 was analyzed and compared with the epitope for the functional mAbs. Previous study implies that hROR1-KNG may be involved in mediating the heterooligomerization between ROR1 and ROR2 in vivo. However, apparently, no direct interaction between hROR1-KNG and hROR2-KNG was observed from chemical shift perturbation experiment. Our work lays foundation to further functional study on interactions of hROR1-KNG with other biological relevant partners.Communicated by Ramaswamy H. Sarma.

    Citation

    Xiaofang Ma, Bin Liu, Jiahui Yang, Kaifeng Hu. Solution structure, dynamics and function investigation of Kringle domain of human receptor tyrosine kinase-like orphan receptor 1. Journal of biomolecular structure & dynamics. 2020 May;38(8):2229-2239

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    PMID: 31232192

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