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发表于 2021-10-9 22:36:37
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晶体结构分析：
4-1BB和BHZ-L-Yr-16-Fc结合位点在4-1BB 的CDR4区(figure 2A). The primary interaction sites of HZ-L-Yr-16 with 4-1BB are located in the CDR2 and CDR3 regions of the vHH. The CDR2 and CDR3 loops form hydrogen bonds with residues D142, R154, V156, C158 and G159 of 4-1BB (figure 2B, online supplemental table 1). Additionally, HZ-L-Yr-16 grips the two β-strands of CRD4 at the hydrophobic pocket formed by the residues V32, A33, Y37, L47, I52, Y97, Y102, Y112 and W115 (online supplemental figure 2A). The binding interface is also mediated by salt bridges between R154 of 4-1BB and D55 or D57 of HZ-LYr-16 (online supplemental figure 2B).Urelumab (PDB: 6MHR) binds to the N-terminus of 4-1BB (CRD1), whereas Utomilumab (PDB: 6MI2) interacts with the domain 3–4 junction.18 HZ-L-Yr-16 binds to the membrane-proximal region and does not appear to interfere with ligand engagement (figure 2C). These differences in binding were consistent with our competitive epitope binning data which shows that HZ-L-Yr-16 does not compete with Urelumab and Utomilumab for binding to 4-1BB (online supplemental figure 3). Interestingly, on binding to ligand or the different antibodies, 4-1BB shows conformational changes by bending between the A2 and A1 motifs of CRD3 (online supplemental figure 2C)
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