4R4B

Crystal structure of the anti-hiv-1 antibody 2.2c

Summary for 4R4B

• Entry DOI: 10.2210/pdb4r4b/pdb
• Related: 4R4F 4R4H 4R4N
• Descriptor: FAB 2.2C LIGHT CHAIN, FAB 2.2C HEAVY CHAIN, SULFATE ION, ... (5 entities in total)
• Functional Keywords: igg, fab, hiv, immunoglobulin domain, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 190812.22

Authors

McLellan, J.S.,Acharya, P.,Huang, C.-C.,Robinson, J.,Kwong, P.D. (deposition date: 2014-08-19, release date: 2014-09-10, Last modification date: 2024-11-27)

Primary citation

Acharya, P.,Tolbert, W.D.,Gohain, N.,Wu, X.,Yu, L.,Liu, T.,Huang, W.,Huang, C.C.,Kwon, Y.D.,Louder, R.K.,Luongo, T.S.,McLellan, J.S.,Pancera, M.,Yang, Y.,Zhang, B.,Flinko, R.,Foulke, J.S.,Sajadi, M.M.,Kamin-Lewis, R.,Robinson, J.E.,Martin, L.,Kwong, P.D.,Guan, Y.,DeVico, A.L.,Lewis, G.K.,Pazgier, M.
Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection.
J.Virol., 88:12895-12906, 2014

PubMed Abstract: The RV144 vaccine trial implicated epitopes in the C1 region of gp120 (A32-like epitopes) as targets of potentially protective antibody-dependent cellular cytotoxicity (ADCC) responses. A32-like epitopes are highly immunogenic, as infected or vaccinated individuals frequently produce antibodies specific for these determinants. Antibody titers, as measured by enzyme-linked immunosorbent assay (ELISA) against these epitopes, however, do not consistently correlate with protection. Here, we report crystal structures of CD4-stabilized gp120 cores complexed with the Fab fragments of two nonneutralizing, A32-like monoclonal antibodies (MAbs), N5-i5 and 2.2c, that compete for antigen binding and have similar antigen-binding affinities yet exhibit a 75-fold difference in ADCC potency. We find that these MAbs recognize overlapping epitopes formed by mobile layers 1 and 2 of the gp120 inner domain, including the C1 and C2 regions, but bind gp120 at different angles via juxtaposed VH and VL contact surfaces. A comparison of structural and immunological data further showed that antibody orientation on bound antigen and the capacity to form multivalent antigen-antibody complexes on target cells were key determinants of ADCC potency, with the latter process having the greater impact. These studies provide atomic-level definition of A32-like epitopes implicated as targets of protective antibodies in RV144. Moreover, these studies establish that epitope structure and mode of antibody binding can dramatically affect the potency of Fc-mediated effector function against HIV-1. These results provide key insights for understanding, refining, and improving the outcome of HIV vaccine trials, in which relevant immune responses are facilitated by A32-like elicited responses.

PubMed: 25165110
DOI: 10.1128/JVI.02194-14

Experimental method

X-RAY DIFFRACTION (2.199 Å)