Computational Prediction of Protein Hot Spot Residues

Morrow, John Kenneth; Zhang, Shuxing

doi:10.2174/138161212799436412

Cited by 84 publications

(35 citation statements)

References 112 publications

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“…This is similar to the hot-spot predictions to determine key interface residues. [64][65][66] We generated DDG predictions for the Prime and MacroModel methods on this data set and utilized predictions using the Discovery Studio method previously determined. 63 The results of these DDG predictions are shown in Supplementary Table 6.…”

Section: Evaluation Of Prediction Methodsmentioning

confidence: 99%

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies. To accomplish this, we solved the co-crystal structures of myostatin with the chimeric (Protein Databank (PDB) id 5F3B) and CDR-grafted antimyostatin antibody (PDB id 5F3H), allowing us to computationally predict the structurally important CDR residues as well as those making significant contacts with the antigen. Structure-based rational design enabled further germlining of the CDR-grafted antibody, reducing the murine content of the antibody without affecting antigen binding. The overall "humanness" was increased for both the light and heavy chain variable regions.

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Section: Evaluation Of Prediction Methodsmentioning

confidence: 99%

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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“…The most common targeted sites are: active sites, allosteric sites, and protein-protein interaction sites. [125, 126] These binding sites present different features, shape and dynamics that sometimes make them difficult to target. A growing number of promising allosteric drugs are showing that structure-based drug design efforts can usefully go beyond the active site region of the protein of interest.…”

Section: Mapping Of Druggable Binding Sitesmentioning

confidence: 99%

Exploring the role of receptor flexibility in structure-based drug discovery

Feixas

Lindert

Sinko

et al. 2014

Biophysical Chemistry

129

131

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The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads.

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“…The rare amino acid residue tryptophan contributes in a disproportionally high frequency to short peptide motifs that mediate protein-protein interactions (54)(55)(56). In the large tegument proteins of the Alphaherpesvirinae, 21 of the 32 tryptophans are con-…”

Section: Discussionmentioning

confidence: 99%

“…Hot spots on protein surfaces are specific amino acid peptide motifs that contribute more than others to the binding affinity of protein-protein interaction interfaces (54)(55)(56). The composition of hot spots is distinctive and not random, with tryptophans (W) having the highest frequency; when tryptophan with its large hydrophobic surface is mutated to alanine (A), the size difference of these residues generates a cavity that creates a local destabilization (54,57,58 …”

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confidence: 99%

Conserved Tryptophan Motifs in the Large Tegument Protein pUL36 Are Required for Efficient Secondary Envelopment of Herpes Simplex Virus Capsids

Ivanova

Buch

Döhner

et al. 2016

J Virol

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Herpes simplex virus (HSV) replicates in the skin and mucous membranes, and initiates lytic or latent infections in sensory neurons. Assembly of progeny virions depends on the essential large tegument protein pUL36 of 3,164 amino acid residues that links the capsids to the tegument proteins pUL37 and VP16. Of the 32 tryptophans of HSV-1-pUL36, the tryptophan-acidic motifs 1766 WD 1767 and 1862 WE 1863 are conserved in all HSV-1 and HSV-2 isolates. Here, we characterized the role of these motifs in the HSV life cycle since the rare tryptophans often have unique roles in protein function due to their large hydrophobic surface. The infectivity of the mutants HSV-1(17 ؉ )Lox-pUL36-WD/AA-WE/AA and HSV-1(17 ؉ )Lox-CheVP26-pUL36-WD/AA-WE/AA, in which the capsid has been tagged with the fluorescent protein Cherry, was significantly reduced. Quantitative electron microscopy shows that there were a larger number of cytosolic capsids and fewer enveloped virions compared to their respective parental strains, indicating a severe impairment in secondary capsid envelopment. The capsids of the mutant viruses accumulated in the perinuclear region around the microtubule-organizing center and were not dispersed to the cell periphery but still acquired the inner tegument proteins pUL36 and pUL37. Furthermore, cytoplasmic capsids colocalized with tegument protein VP16 and, to some extent, with tegument protein VP22 but not with the envelope glycoprotein gD. These results indicate that the unique conserved tryptophan-acidic motifs in the central region of pUL36 are required for efficient targeting of progeny capsids to the membranes of secondary capsid envelopment and for efficient virion assembly. IMPORTANCEHerpesvirus infections give rise to severe animal and human diseases, especially in young, immunocompromised, and elderly individuals. The structural hallmark of herpesvirus virions is the tegument, which contains evolutionarily conserved proteins that are essential for several stages of the herpesvirus life cycle. Here we characterized two conserved tryptophan-acidic motifs in the central region of the large tegument protein pUL36 of herpes simplex virus. When we mutated these motifs, secondary envelopment of cytosolic capsids and the production of infectious particles were severely impaired. Our data suggest that pUL36 and its homologs in other herpesviruses, and in particular such tryptophan-acidic motifs, could provide attractive targets for the development of novel drugs to prevent herpesvirus assembly and spread. T he diversity of clinical herpesvirus isolates is shaped to a large extent by the long coevolution between virus and host as well as by homologous recombination among different strains (1-4). The subfamilies of the Herpesviridae are characterized by similar properties: for example, fast replication of members of the Alphaherpesvirinae in keratinocytes, epithelial cells, or fibroblasts and latency in sensory neurons. Infections with the herpes simplex viruses (HSV-1 or HSV-2) or varicella-zoster virus occur...

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Computational Prediction of Protein Hot Spot Residues

Cited by 84 publications

References 112 publications

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Exploring the role of receptor flexibility in structure-based drug discovery

Conserved Tryptophan Motifs in the Large Tegument Protein pUL36 Are Required for Efficient Secondary Envelopment of Herpes Simplex Virus Capsids

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