Hiding in plain sight: structure and sequence analysis reveals the importance of the antibody DE loop for antibody-antigen binding.
MAbs
; 12(1): 1840005, 2020.
Article
em En
| MEDLINE
| ID: mdl-33180672
ABSTRACT
Antibody variable domains contain "complementarity-determining regions" (CDRs), the loops that form the antigen binding site. CDRs1-3 are recognized as the canonical CDRs. However, a fourth loop sits adjacent to CDR1 and CDR2 and joins the D and E strands on the antibody v-type fold. This "DE loop" is usually treated as a framework region, even though mutations in the loop affect the conformation of the CDRs and residues in the DE loop occasionally contact antigen. We analyzed the length, structure, and sequence features of all DE loops in the Protein Data Bank (PDB), as well as millions of sequences from HIV-1 infected and naïve patients. We refer to the DE loop as H4 and L4 in the heavy and light chains, respectively. Clustering the backbone conformations of the most common length of L4 (6 residues) reveals four conformations two κ-only clusters, one λ-only cluster, and one mixed κ/λ cluster. Most H4 loops are length-8 and exist primarily in one conformation; a secondary conformation represents a small fraction of H4-8 structures. H4 sequence variability exceeds that of the antibody framework in naïve human high-throughput sequences, and both L4 and H4 sequence variability from λ and heavy germline sequences exceed that of germline framework regions. Finally, we identified dozens of structures in the PDB with insertions in the DE loop, all related to broadly neutralizing HIV-1 antibodies (bNabs), as well as antibody sequences from high-throughput sequencing studies of HIV-infected individuals, illuminating a possible role in humoral immunity to HIV-1.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Modelos Moleculares
/
Regiões Determinantes de Complementaridade
/
Reações Antígeno-Anticorpo
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
MAbs
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos