7TI6

Crystal structure of the wild-type least mutated common ancestor (LMCA) of the HIV-targeting PCT64 antibody lineage

Summary for 7TI6

• Entry DOI: 10.2210/pdb7ti6/pdb
• Descriptor: PCT64_LMCA Fab heavy chain, PCT64_LMCA light chain (wild type), 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: antibody, broadly neutralizing, hiv-1, v2 apex, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 49346.84

Authors

Omorodion, O.,Wilson, I.A. (deposition date: 2022-01-12, release date: 2022-10-05, Last modification date: 2024-10-23)

Primary citation

Willis, J.R.,Berndsen, Z.T.,Ma, K.M.,Steichen, J.M.,Schiffner, T.,Landais, E.,Liguori, A.,Kalyuzhniy, O.,Allen, J.D.,Baboo, S.,Omorodion, O.,Diedrich, J.K.,Hu, X.,Georgeson, E.,Phelps, N.,Eskandarzadeh, S.,Groschel, B.,Kubitz, M.,Adachi, Y.,Mullin, T.M.,Alavi, N.B.,Falcone, S.,Himansu, S.,Carfi, A.,Wilson, I.A.,Yates 3rd, J.R.,Paulson, J.C.,Crispin, M.,Ward, A.B.,Schief, W.R.
Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.
Immunity, 55:2149-2167.e9, 2022

PubMed Abstract: Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.

PubMed: 36179689
DOI: 10.1016/j.immuni.2022.09.001

Experimental method

X-RAY DIFFRACTION (2.64 Å)