Structural repertoire of the human VH segments

Cyrus Chothia, Arthur M. Lesk, Ermanno Gherardi, Ian M. Tomlinson, Gerald Walter, James D. Marks, Meirion B. Llewelyn, Greg Winter

Research output: Contribution to journalArticlepeer-review

357 Scopus citations

Abstract

The VH gene segments produce the part of the VH domains of antibodies that contains the first two hypervariable regions. The sequences of 83 human VH segments with open reading frames, from several individuals, are currently known. It has been shown that these sequences are likely to form a high proportion of the total human repertoire and that an individual's gene repertoire produces about 50 VH segments with different protein sequences. In this paper we present a structural analysis of the amino acid sequences produced by the 83 segments. Particular residue patterns in the sequences of V domains imply particular main-chain conformations, canonical structures, for the hypervariable regions. We show that, in almost all cases, the residue patterns in the VH segments imply that the first hypervariable regions have one of three different canonical structures and that the second hypervariable regions have one of five different canonical structures. The different observed combinations of the canonical structures in the first and second regions means that almost all sequences have one of seven main-chain folds. We describe, in outline, structures of the antigen binding site loops produced by nearly all the VH segments. The exact specificity of the loops is produced by (1) sequence differences in their surface residues, particularly at sites near the centre of the combining site, and (2) sequence differences in the hypervariable and framework regions that modulate the relative positions of the loops.

Original languageEnglish (US)
Pages (from-to)799-817
Number of pages19
JournalJournal of Molecular Biology
Volume227
Issue number3
DOIs
StatePublished - Oct 5 1992

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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