Structural highlights
FunctionPublication Abstract from PubMedThe 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 degrees 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 pi-cation sandwiching the V3 crown apex residue Arg315, and (iii) a salt bridge between the 447-52D heavy chain residue AspH95 and Arg315. Arg315 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. Thermodynamic Signatures of the Antigen Binding Site of mAb 447-52D Targeting the Third Variable Region of HIV-1 gp120.,Killikelly A, Zhang HT, Spurrier B, Williams C, Gorny MK, Zolla-Pazner S, Kong XP Biochemistry. 2013 Aug 23. PMID:23944979[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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