6ay2

Structure of CathB with covalently linked Compound 28

spinqualitylabelsall models 6ay2, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ay2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: C1G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CATB_HUMAN Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. Publication Abstract from PubMed Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs. Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity.,Wei B, Gunzner-Toste J, Yao H, Wang T, Wang J, Xu Z, Chen J, Wai J, Nonomiya J, Tsai SP, Chuh J, Kozak KR, Liu Y, Yu SF, Lau J, Li G, Phillips GD, Leipold D, Kamath A, Su D, Xu K, Eigenbrot C, Steinbacher S, Ohri R, Raab H, Staben LR, Zhao G, Flygare JA, Pillow TH, Verma V, Safina B J Med Chem. 2017 Dec 21. doi: 10.1021/acs.jmedchem.7b01430. PMID:29227683 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cathepsin 3D structures

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