9PZ6
Anti-NANP Fab with G112T light chain mutation
Summary for 9PZ6
| Entry DOI | 10.2210/pdb9pz6/pdb |
| Descriptor | IgG heavy chain, IgG light chain, TRIETHYLENE GLYCOL, ... (6 entities in total) |
| Functional Keywords | nanp, antibody, fab, lambda, immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 48009.58 |
| Authors | |
| Primary citation | Jewel, Y.,Young, T.,Park, M.,Ly, K.,Gonzalez, A.,Mallett, T.C.,Williams, J.C. Single-residue engineering of lambda ( lambda ) antibody light chains reduces conformational flexibility and enhances thermal stability. Comput Struct Biotechnol J, 27:4730-4739, 2025 Cited by PubMed Abstract: Monoclonal antibodies with lambda (λ) light chains are less commonly used in therapeutics due to their lower biophysical stability compared to kappa (κ) variants. Here, we identify a conserved glycine residue (Gly111) in the λ light chain hinge as a driver of large-scale Fab elbow-angle transitions. Using microsecond-scale molecular dynamics simulations of the EBV-neutralizing Fab AMMO1, we show that substituting Gly111 with threonine (G111T) increases the free energy barrier between conformational states, effectively arresting these transitions. Structural and biophysical analyses-including crystallography, differential scanning fluorimetry, and surface plasmon resonance-confirm that the mutation maintains Fab architecture and antigen binding while increasing thermal stability by up to 2.5 °C. The same mutation applied to a second λ-Fab yielded similar stabilization, and simulations of three clinical λ-Fabs revealed consistent reductions in elbow-angle flexibility. These results demonstrate a generalizable, single-residue engineering strategy to enhance the stability of λ-based Fabs without compromising function, with direct implications for therapeutic antibody development and manufacturability. PubMed: 41245890DOI: 10.1016/j.csbj.2025.10.045 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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