4RIS

Structural Analysis of the Unmutated Ancestor of the HIV-1 Envelope V2 Region Antibody CH58 Isolated From an RV144 HIV-1 Vaccine Efficacy Trial Vaccinee and Associated with Decreased Transmission Risk

Summary for 4RIS

• Entry DOI: 10.2210/pdb4ris/pdb
• Related: 4RIR
• Descriptor: Envelope glycoprotein, CH58-UA Fab heavy chain, CH58-UA Fab light chain, ... (4 entities in total)
• Functional Keywords: antibody, igg fold, immune system, hiv-1 gp120 v2 region
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 50256.80

Authors

Nicely, N.I.,Wiehe, K.,Kepler, T.B.,Jaeger, F.H.,Dennison, S.M.,Liao, H.-X.,Alam, S.M.,Hwang, K.-K.,Bonsignori, M.,Rerks-Ngarm, S.,Nitayaphan, S.,Pitisuttithum, P.,Kaewkungwal, J.,Robb, M.L.,O'Connell, R.J.,Michael, N.L.,Kim, J.H.,Haynes, B.F. (deposition date: 2014-10-07, release date: 2015-08-12, Last modification date: 2015-09-02)

Primary citation

Nicely, N.I.,Wiehe, K.,Kepler, T.B.,Jaeger, F.H.,Dennison, S.M.,Rerks-Ngarm, S.,Nitayaphan, S.,Pitisuttithum, P.,Kaewkungwal, J.,Robb, M.L.,O'Connell, R.J.,Michael, N.L.,Kim, J.H.,Liao, H.X.,Munir Alam, S.,Hwang, K.K.,Bonsignori, M.,Haynes, B.F.
Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.
EBioMedicine, 2:713-722, 2015

PubMed Abstract: Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets infected with CRF_01 AE tier 2 virus. CH58 and other antibodies that bind to a gp120 V2 epitope have a second light chain complementarity determining region (LCDR2) bearing a glutamic acid, aspartic acid (ED) motif involved in forming salt bridges with polar, basic side amino acid side chains in V2. In an effort to learn how V2 responses develop, we determined the crystal structures of the CH58-UA antibody unliganded and bound to V2 peptide. The structures showed an LCDR2 structurally pre-conformed from germline to interact with V2 residue Lys169. LCDR3 was subject to conformational selection through the affinity maturation process. Kinetic analyses demonstrate that only a few contacts were responsible for a 2000-fold increase in KD through maturation, and this effect was predominantly due to an improvement in off-rate. This study shows that preconformation and preconfiguration can work in concert to produce antibodies with desired immunogenic properties.

PubMed: 26288844
DOI: 10.1016/j.ebiom.2015.06.016

Experimental method

X-RAY DIFFRACTION (2.3 Å)