4M1D

Crystal structure of anti-HIV-1 Fab 447-52D in complex with V3 cyclic peptide MN

Summary for 4M1D

• Entry DOI: 10.2210/pdb4m1d/pdb
• Descriptor: Fab mAb 447-52D Light Chain, Fab mAb 447-52D Heavy Chain, Cyclic V3 Arch Peptide, ... (5 entities in total)
• Functional Keywords: hiv, v3 loop, antibody-antigen interactions, envelope, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 99861.45

Authors

Killikelly, A.,Kong, X.P. (deposition date: 2013-08-02, release date: 2013-09-04, Last modification date: 2024-10-09)

Primary citation

Killikelly, A.,Zhang, H.T.,Spurrier, B.,Williams, C.,Gorny, M.K.,Zolla-Pazner, S.,Kong, X.P.
Thermodynamic Signatures of the Antigen Binding Site of mAb 447-52D Targeting the Third Variable Region of HIV-1 gp120.
Biochemistry, 52:6249-6257, 2013

PubMed Abstract: The third variable region (V3) of HIV-1 gp120 plays a key role in viral entry into host cells; thus, it is a potential target for vaccine design. Human monoclonal antibody (mAb) 447-52D is one of the most broadly and potently neutralizing anti-V3 mAbs. We further characterized the 447-52D epitope by determining a high-resolution crystal structure of the Fab fragment in complex with a cyclic V3 and interrogated the antigen-antibody interaction by a combination of site-specific mutagenesis, isothermal titration calorimetry (ITC) and neutralization assays. We found that 447-52D's neutralization capability is correlated with its binding affinity and at 25 °C the Gibbs free binding energy is composed of a large enthalpic component and a small favorable entropic component. The large enthalpic contribution is due to (i) an extensive hydrogen bond network, (ii) a π-cation sandwiching the V3 crown apex residue Arg(315), and (iii) a salt bridge between the 447-52D heavy chain residue Asp(H95) and Arg(315). Arg(315) is often harbored by clade B viruses; thus, our data explained why 447-52D preferentially neutralizes clade B viruses. Interrogation of the thermodynamic signatures of residues at the antigen binding interface gives key insights into their contributions in the antigen-antibody interaction.

PubMed: 23944979
DOI: 10.1021/bi400645e

Experimental method

X-RAY DIFFRACTION (1.8 Å)