Antibody-antigen Interactions: Contact Analysis and Binding Site Topography

MacCallum, Robert M.; Martin, Andrew C.R.; Thornton, Janet M.

doi:10.1006/jmbi.1996.0548

Cited by 433 publications

(377 citation statements)

References 29 publications

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“…This is consistent with the trend that has been observed to date in Ab-Ag complexes (3,29,30). In all the three complexes, the epitope is present in a groove in the Ag-combining site, as has been observed for other Ab-peptide complexes (2,31,32). The PC283 paratope surface, however, shows a number of features unique from that seen in the other two Abs.…”

Section: Ag-ab Interactionssupporting

confidence: 89%

Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Nair

Singh

Siddiqui

et al. 2002

The Journal of Immunology

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Crystal structures of distinct mAbs that recognize a common epitope of a peptide Ag have been determined and analyzed in the unbound and bound forms. These Abs display dissimilar binding site structures in the absence of the Ag. The dissimilarity is primarily expressed in the conformations of complementarity-determining region H3, which is responsible for defining the epitope specificity. Interestingly, however, the three Abs exhibit similar complementarity-determining region conformations in the Ag binding site while recognizing the common epitope, indicating that different pathways of binding are used for Ag recognition. The epitope also exhibits conformational similarity when bound to each of these Abs, although the peptide Ag was otherwise flexible. The observed conformational convergence in the epitope and the Ag binding site was facilitated by the plasticity in the nature of interactions.

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Section: Ag-ab Interactionssupporting

confidence: 89%

Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Nair

Singh

Siddiqui

et al. 2002

The Journal of Immunology

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“…The paratopes of conventional antibodies directed against folded proteins tend to be flat or concave; 104 convex binding sites are difficult to achieve, at least by murine and human conventional antibodies, although synthetic conventional antibodies can be engineered to adopt such geometries. 105 By contrast, sdAb paratopes can clearly adopt both flat 106,107 and convex 11 topologies, although possibly only inefficiently adopt concave ones.…”

Section: Single-domain Antibody Paratope Structuresmentioning

confidence: 99%

“…113–115 Similarly, conventional antibodies tend to accommodate short linear peptides and nucleic acid polymers within grooves formed from both heavy- and light-chain CDRs. 104 Four studies have reported structures of camelid V H Hs in complex with haptens and peptides (Table 2); the recognition mechanism of all but one (a methotrexate-specific V H H with a non-canonical binding site involving framework region (FR)3 residues located below CDR1 113 ) was basically similar to that of conventional antibodies, with the hapten-binding pocket formed from two or more CDRs and extending in some instances into the former V L interface. Notably, three of these V H Hs have non-canonical structures of either CDR1 or CDR2 that have not been observed in structures of other V H Hs and may not be germline-encoded.…”

Section: Single-domain Antibodies Directed Against Small Moleculesmentioning

confidence: 99%

Antigen recognition by single-domain antibodies: structural latitudes and constraints

Henry

MacKenzie

2018

mAbs

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Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH:VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. Here, we comprehensively surveyed the evidence in support of this hypothesis. We found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies: sdAb paratopes have smaller molecular surface areas and diameters, more commonly have non-canonical CDR1 and CDR2 structures, and have elongated CDR3 length distributions, but have similar amino acid compositions and are no more extended (interatomic distance measured from CDR base to tip) than conventional antibody paratopes. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.

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“…In other antibodies (Fab fragments) analyzed by X-ray crystallography, [24][25][26] those having hapten-like antigens exhibited CDRs characterized by a deep pocket. Those binding to polypeptide and protein antigens had a flatter, less concave, sometimes even convex surface.…”

Section: Discussionmentioning

confidence: 99%

The Structure of an Antitumor CH2-domain-deleted Humanized Antibody

Larson

Day

Glaser

et al. 2005

Journal of Molecular Biology

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C H 2-domain-deleted CC49 (HuCC49DCH2), a recombinant humanized antibody that recognizes the TAG-72 antigen expressed on a variety of human carcinomas, is secreted from cultured cells as a mixture of two homodimeric isoforms. Isoform A contains two covalent interchain disulfide bonds at heavy chain positions 239 and 242, while isoform B fails to develop any interchain disulfide bonds but has 239-242 intrachain disulfide bonds instead. Form A is currently in preclinical development as a therapeutic agent for treating colorectal carcinoma, though form B shows equal efficacy.HuCC49DCH2 form B can be crystallized from sodium formate only in the presence of detergents. X-ray diffraction data were collected on a single cryo-cooled crystal grown with Triton X-100 and the structure was solved by molecular replacement. The model has refined to RZ0.246 (R free Z0.297) for 2.8 Å data. The antibodies pack in the crystal around crystallographic 2-fold axes as tetramers with approximate 222 symmetry. Atomic force microscopy studies show that this tetrameric structure is the crystal building block and also exists free in the mother liquor. The tetramer is composed of two rings, back-to-back, with a thickness of w83 Å . Each ring is composed of two antibodies with the complementarity-determining regions (CDR) of the two Fabs of one antibody interacting with the CDR regions of the second antibody in a head-to-head fashion. These rings are approximately 167 Å long and 112 Å wide. The C H 3 domain is inverted with respect to the Fabs when compared to the usual orientation found in conventional antibodies. The polypeptides joining the C H 3 domains to the Fab portions of the antibody are not seen and are almost certainly disordered. The antigen combining site of HuCC49DCH2 is very similar, but not identical, in topology and charge distribution to that of antibody B72.3, which binds a similar epitope on TAG-72. The combining site consists of a deep cleft, heavily lined with aromatic amino acid side-chains but bounded by numerous charged groups.

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Antibody-antigen Interactions: Contact Analysis and Binding Site Topography

Cited by 433 publications

References 29 publications

Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Antigen recognition by single-domain antibodies: structural latitudes and constraints

The Structure of an Antitumor CH2-domain-deleted Humanized Antibody

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