Unraveling hot spots in binding interfaces: progress and challenges

DeLano, Warren L.

doi:10.1016/s0959-440x(02)00283-x

Cited by 682 publications

(467 citation statements)

References 46 publications

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“…To visualize the contribution of each serotype in the context of the assembled M41 capsid icosahedral 2-, 3-, and 5-fold symmetry operators were applied to the VP3 model coordinates by matrix multiplication using the program O (36). The serotype segments were then highlighted in the context of 9 VP3 monomers which surround 1 viral asymmetric unit in a surface rendered depiction generated using the program PyMol (35).…”

Section: Methodsmentioning

confidence: 99%

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection

Yang

Jiang

Drouin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

164

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To engineer gene vectors that target striated muscles after systemic delivery, we constructed a random library of adeno-associated virus (AAV) by shuffling the capsid genes of AAV serotypes 1 to 9, and screened for muscle-targeting capsids by direct in vivo panning after tail vein injection in mice. After 2 rounds of in vivo selection, a capsid gene named M41 was retrieved mainly based on its high frequency in the muscle and low frequency in the liver. Structural analyses revealed that the AAVM41 capsid is a recombinant of AAV1, 6, 7, and 8 with a mosaic capsid surface and a conserved capsid interior. AAVM41 was then subjected to a sideby-side comparison to AAV9, the most robust AAV for systemic heart and muscle gene delivery; to AAV6, a parental AAV with strong muscle tropism. After i.v. delivery of reporter genes, AAVM41 was found more efficient than AAV6 in the heart and muscle, and was similar to AAV9 in the heart but weaker in the muscle. In fact, the myocardium showed the highest gene expression among all tissues tested in mice and hamsters after systemic AAVM41 delivery. However, gene transfer in non-muscle tissues, mainly the liver, was dramatically reduced. AAVM41 was further tested in a genetic cardiomyopathy hamster model and achieved efficient long-term ␦-sarcoglycan gene expression and rescue of cardiac functions. Thus, direct in vivo panning of capsid libraries is a simple tool for the de-targeting and retargeting of viral vector tissue tropisms facilitated by acquisition of desirable sequences and properties.

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Section: Methodsmentioning

confidence: 99%

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection

Yang

Jiang

Drouin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

164

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“…Mapping studies have located energetic residues in "hot spots" of epitopes and paratopes, i.e. regions made up of small numbers of residues that contribute most of the binding energy [49]. Energetic residues are often located in the center of the epitopeparatope interface [50].…”

Section: Structural and Functional Definition Of An Epitopementioning

confidence: 99%

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

2006

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HLAMatchmaker is a structurally based matching program. Each HLA antigen is viewed as a string of epitopes represented by short sequences (triplets) involving polymorphic amino acid residues in antibody-accessible positions. HLAMatchmaker determines which triplets are different between donor and recipient and this algorithm is clinically useful in determining HLA mismatch acceptability. Triplets provide however an incomplete description of the HLA epitope repertoire and expanded criteria must be used including longer sequences and polymorphic residues in discontinuous positions. Such criteria should consider the structural basis of antibody-antigen interactions including contact areas and binding energy, the essence of antigenicity.This report describes the development of a structurally defined HLA epitope repertoire based on stereochemical modeling of crystallized complexes of antibodies and different protein antigens. This analysis considered also data in the literature about contributions of amino acid residues to antigenantibody binding energy. The results have led to the concept that HLA antigens like other antigenic proteins have structural epitopes consisting of 15-22 residues that constitute the binding face with alloantibody. Each structural epitope has a functional epitope of about 2-5 residues that dominate the strength and specificity of binding with antibody. The remaining residues of a structural epitope provide supplementary interactions that increase the stability of the antigen-antibody complex. Each functional epitope has one or more non-self residues and the term "eplet" is used to describe polymorphic HLA residues within 3.0-3.5 Ångstroms of a given sequence position on the molecular surface. Many eplets represent short linear sequences identical to those referred to as triplets but others have residues in discontinuous sequence positions that cluster together on the molecular surface. Serologically defined HLA determinants correspond well to eplets. The eplet version of HLAMatchmaker represents therefore a more complete repertoire of structurally defined HLA epitopes and provides a more detailed assessment of HLA compatibility.

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“…First, peptide epitopes can involve a single region of a polypeptidesuch as an a-helix from one face lying in a groove on the opposite face -or a series of discontinuous segments from one or more protein domains. Second, while the physical interface is typified by a large number of polar and nonpolar interactions, their individual contributions are not uniform Cunningham et al 1989;DeLano 2002a;Ofran and Rost 2007;London et al 2010). PPIs tend to contain a small number of residues -termed hotspots -that are responsible for the majority of binding strength (Fig.…”

Section: Introductionmentioning

confidence: 99%