9J4C
Cryo-EM structure of aPlexinA1-19-43 Fab in complex with PlexinA1 dimer
Summary for 9J4C
| Entry DOI | 10.2210/pdb9j4c/pdb |
| EMDB information | 61131 |
| Descriptor | Plexin-A1, Light chain of aPlexinA1-19-43 Fab, Heavy chain of aPlexinA1-19-43 Fab (3 entities in total) |
| Functional Keywords | signalling, fab, complex, protein binding, protein binding-immune system complex, protein binding/immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 125426.62 |
| Authors | |
| Primary citation | Tian, H.,Fung, C.P.,Burman, L.,Chong, Y.E.,Liu, C.,Geng, Y.,Yang, L.,Chow, M.W.,Zhang, Y.,Ho, K.W.H.,Zhu, G.,Wu, Z.,Yang, X.L.,Xu, Z.,Nangle, L.A. A bispecific antibody designed to act as a NRP2/PLXNA1 agonist mimics anticancer activity of SEMA3F. J.Biol.Chem., 302:111056-111056, 2025 Cited by PubMed Abstract: Neuropilin-2 (NRP2) is a pleiotropic receptor with diverse roles across biological systems. Recent work detailed its role as an immunomodulatory receptor target that is currently being explored in clinical development for interstitial lung diseases, establishing it as a viable therapeutic target. To mediate its diverse effects, NRP2 interacts with endogenous ligands, including semaphorins (SEMAs) and vascular endothelial growth factors, signaling via ligand-induced heterodimerization with various receptor families. One of these ligands, SEMA3F exhibits well-documented tumor-suppressive activities mediated through NRP2 and plexinA1 (PLXNA1). Despite its observed benefits, SEMA3F is not therapeutically viable due to the multifaceted nature of its functions through non-NRP2-mediated interactions, leading to concerns around potential toxicity. Here, we describe development of bispecific antibodies (bsAbs) that dimerize PLXNA1 and NRP2, selectively mimicking the beneficial aspects of SEMA3F signaling as a basis for a novel anticancer therapy. Using a single B cell-based mAb discovery platform, anti-PLXNA1 mAbs with diverse lineages were generated and combined with anti-NRP2 mAbs to produce over 200 PLXNA1-NRP2 bsAbs. Antibodies were screened in cell-based assays (receptor dimerization, phospho-AKT, oncogene expression, and cell proliferation), yielding one bsAb capable of mimicking NRP2-mediated SEMA3F activities in all assays. Structural studies revealed that this bsAb binds to PLXNA1/NRP2 at sites distinct from the SEMA3F-binding site, but in a manner that allows proper spacing for receptor complex formation and flexibility of conformational changes for signaling. This study demonstrates the potential of these receptors as targets for agonistic bsAbs development and provides the groundwork for further exploration in tumor models. PubMed: 41391772DOI: 10.1016/j.jbc.2025.111056 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.33 Å) |
Structure validation
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