Biomaterial Database

Conformations of the third hypervariable region in the VH domain of immunoglobulins. 1998

V Morea, and A Tramontano, and M Rustici, and C Chothia, and A M Lesk

Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Roma, Italy.

Antigen-combining sites of antibodies are constructed from six loops from VL and VH domains. The third hypervariable region of the heavy chain is far more variable than the others in length, sequence and structure, and was not included in the canonical-structure description of the conformational repertoire of the three hypervariable regions of V kappa chains and the first two of VH chains. Here we present an analysis of the conformations of the third hypervariable region of VH domains (the H3 regions) in antibodies of known structure. We define the H3 region as comprising the residues between 92Cys and 104Gly. We divide it into a torso comprising residues proximal to the framework, four residues from the N terminus and six residues from the C terminus, and a head. There are two major classes of H3 structures that have more than ten residues between 92Cys and 104Gly: (1) the conformation of the torso has a beta-bulge at residue 101, and (2) the torso does not contain a bulge, but continues the regular hydrogen-bonding pattern of the beta-sheet hairpin. The choice of bulged versus non-bulged torso conformation is dictated primarily by the sequence, through the formation of a salt bridge between the side-chains of an Arg or Lys at position 94 and an Asp at position 101. Thus the torso region appears to have a limited repertoire of conformations, as in the canonical structure model of other antigen-binding loops. The heads or apices of the loops have a very wide variety of conformations. In shorter H3 regions, and in those containing the non-bulged torso conformation, the heads follow the rules relating sequence to structure in short hairpins. We surveyed the heads of longer H3 regions, finding that those with bulged torsos present many very different conformations of the head. We recognize that H3, unlike the other five antigen-binding loops, has a conformation that depends strongly on the environment, and we have analysed the interactions of H3 with residues elsewhere in the VH domain, in the VL domain, and with ligands, and their effects on the conformation of H3. We tested these results by attempts to predict the conformations of H3 regions in antibody structures solved after the results were derived. The general conclusion of this work is that the conformation of H3 shows some regularities, from which rules relating sequence to conformation can be stated, but to a less complete degree than for the other five antigen-binding loops. Accurate prediction of the torso conformation is possible in most cases; predictions of the conformation of the head is possible in some cases. However, our understanding of the sequence-structure relationships has reduced the uncertainty to no more than a few residues at the apex of the H3 region.

UI	MeSH Term	Description	Entries
D007135	Immunoglobulin Variable Region	That region of the immunoglobulin molecule that varies in its amino acid sequence and composition, and comprises the binding site for a specific antigen. It is located at the N-terminus of the Fab fragment of the immunoglobulin. It includes hypervariable regions (COMPLEMENTARITY DETERMINING REGIONS) and framework regions.	Variable Region, Ig,Variable Region, Immunoglobulin,Framework Region, Immunoglobulin,Fv Antibody Fragments,Fv Fragments,Ig Framework Region,Ig Variable Region,Immunoglobulin Framework Region,Immunoglobulin Fv Fragments,Immunoglobulin V,Antibody Fragment, Fv,Antibody Fragments, Fv,Fragment, Fv,Fragment, Fv Antibody,Fragment, Immunoglobulin Fv,Fragments, Fv,Fragments, Fv Antibody,Fragments, Immunoglobulin Fv,Framework Region, Ig,Framework Regions, Ig,Framework Regions, Immunoglobulin,Fv Antibody Fragment,Fv Fragment,Fv Fragment, Immunoglobulin,Fv Fragments, Immunoglobulin,Ig Framework Regions,Ig Variable Regions,Immunoglobulin Framework Regions,Immunoglobulin Fv Fragment,Immunoglobulin Variable Regions,Regions, Immunoglobulin Variable,Variable Regions, Ig,Variable Regions, Immunoglobulin
D007143	Immunoglobulin Heavy Chains	The largest of polypeptide chains comprising immunoglobulins. They contain 450 to 600 amino acid residues per chain, and have molecular weights of 51-72 kDa.	Immunoglobulins, Heavy-Chain,Heavy-Chain Immunoglobulins,Ig Heavy Chains,Immunoglobulin Heavy Chain,Immunoglobulin Heavy Chain Subgroup VH-I,Immunoglobulin Heavy Chain Subgroup VH-III,Heavy Chain Immunoglobulins,Heavy Chain, Immunoglobulin,Heavy Chains, Ig,Heavy Chains, Immunoglobulin,Immunoglobulin Heavy Chain Subgroup VH I,Immunoglobulin Heavy Chain Subgroup VH III,Immunoglobulins, Heavy Chain
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011487	Protein Conformation	The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).	Conformation, Protein,Conformations, Protein,Protein Conformations
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D000595	Amino Acid Sequence	The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.	Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D016208	Databases, Factual	Extensive collections, reputedly complete, of facts and data garnered from material of a specialized subject area and made available for analysis and application. The collection can be automated by various contemporary methods for retrieval. The concept should be differentiated from DATABASES, BIBLIOGRAPHIC which is restricted to collections of bibliographic references.	Databanks, Factual,Data Banks, Factual,Data Bases, Factual,Data Bank, Factual,Data Base, Factual,Databank, Factual,Database, Factual,Factual Data Bank,Factual Data Banks,Factual Data Base,Factual Data Bases,Factual Databank,Factual Databanks,Factual Database,Factual Databases