9VXL
CD38 in complex with 028 Fab
Summary for 9VXL
| Entry DOI | 10.2210/pdb9vxl/pdb |
| Descriptor | heavy chain of 028, light chain of 028, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (3 entities in total) |
| Functional Keywords | car, cd38, antibody, membrane protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 3 |
| Total formula weight | 73809.94 |
| Authors | |
| Primary citation | Cheng, Z.,Zhang, L.,Liang, Z.,Huang, Q.,Tang, Z.,Shi, X.,Liu, L.,Yang, G.,Yan, L. Structural dissection of CD38 antigen engagement by CAR binders and rational affinity tuning. Iscience, 29:115937-115937, 2026 Cited by PubMed Abstract: Chimeric antigen receptor (CAR) T cell therapy uses synthetic receptors to direct T cells to target and lyse cancer cells. CD38 is a multifunctional ectoenzyme involved in immunomodulation and a therapeutic target in hematological malignancies. Here, we report structural and functional characterization of two CD38-targeting binders, RP02 and 028, revealing distinct mechanisms of epitope engagement and enzymatic inhibition. Crystal structures demonstrate that RP02 binds the N-lobe of CD38 via VH-mediated interactions, while 028 spans both N- and C-lobes, inducing allosteric inhibition. Alanine scanning identified critical residues for affinity tuning. Functional assays showed 028 potently inhibits CD38's cyclase activity, whereas RP02 has minimal effect, correlating with 028's occlusion of the catalytic pocket via η6 loop-mediated dimerization. Further, CAR-T cells engineered with affinity-attenuated 028 exhibited reduced fratricide while retaining cytotoxicity against CD38 tumors. Our work delineates structure-guided strategies to optimize CD38-targeted therapeutics by balancing affinity, inhibition, and cellular selectivity. PubMed: 42256285DOI: 10.1016/j.isci.2026.115937 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.15 Å) |
Structure validation
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