SiteMine: Large‐scale binding site similarity searching in protein structure databases

Reim, Thorben; Ehrt, Christiane; Graef, Joel; Günther, Sebastian; Meents, Alke; Rarey, Matthias

doi:10.1002/ardp.202300661

Cited by 4 publications

(1 citation statement)

References 71 publications

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“…Alignment Algorithm. We developed the new algorithmic concept of TetraScan for binding site 28 and protein-protein interface comparisons. Here, we describe the method in the context of interface similarity.…”

Section: ■ Introductionmentioning

confidence: 99%

Database-Driven Identification of Structurally Similar Protein-Protein Interfaces

Graef,

Ehrt,

Reim

et al. 2024

J. Chem. Inf. Model.

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Analyzing the similarity of protein interfaces in proteinprotein interactions gives new insights into protein function and assists in discovering new drugs. Usually, tools that assess the similarity focus on the interactions between two protein interfaces, while sometimes we only have one predicted interface. Herein, we present PiMine, a database-driven protein interface similarity search. It compares interface residues of one or two interacting chains by calculating and searching tetrahedral geometric patterns of α-carbon atoms and calculating physicochemical and shape-based similarity. On a dedicated, tailormade dataset, we show that PiMine outperforms commonly used comparison tools in terms of early enrichment when considering interfaces of sequentially and structurally unrelated proteins. In an application example, we demonstrate its usability for protein interaction partner prediction by comparing predicted interfaces to known protein-protein interfaces.

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Section: ■ Introductionmentioning

confidence: 99%

Database-Driven Identification of Structurally Similar Protein-Protein Interfaces

Graef,

Ehrt,

Reim

et al. 2024

J. Chem. Inf. Model.

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SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery

Kremling,

Falke,

Fernández-García

et al. 2024

Preprint

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Non-structural protein 10 (nsp10) and non-structural protein 16 (nsp16) are part of the RNA synthesis complex, which is crucial for the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nsp16 exhibits 2-O-methyltransferase activity during viral messenger RNA capping and is active in a heterodimeric complex with enzymatically inactive nsp10. It has been shown that inactivation of the nsp10-16 protein complex interferes severely with viral replication, making it a highly promising drug target. As information on ligands binding to the nsp10-16 complex (nsp10-16) is still scarce, we screened the active site for potential binding of drug-like and fragment-like compounds using X-ray crystallography. The screened set of 244 compounds consists of derivatives of the natural substrate S-adenosyl methionine (SAM) and adenine derivatives, of which some have been described previously as methyltransferase inhibitors and nsp16 binders. A docking study guided the selection of many of these compounds. Here we report structures of binders to the SAM site of nsp10-16 and for two of them, toyocamycin and sangivamycin, we present additional crystal structures in the presence of a second substrate, Cap0-analog/Cap0-RNA. The identified hits were tested for binding to nsp10-16 in solution and antiviral activity in cell culture. Our data provide important structural information on various molecules that bind to the SAM substrate site which can be used as novel starting points for selective methyltransferase inhibitor designs.

show abstract

SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery

Kremling,

Falke,

Fernández-García

et al. 2024

Preprint

View full text Add to dashboard Cite

Non-structural protein 10 (nsp10) and non-structural protein 16 (nsp16) are part of the RNA synthesis complex, which is crucial for the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nsp16 exhibits 2’- O -methyltransferase activity during viral messenger RNA capping and is active in a heterodimeric complex with enzymatically inactive nsp10. It has been shown that inactivation of the nsp10-16 protein complex interferes severely with viral replication, making it a highly promising drug target. As information on ligands binding to the nsp10-16 complex (nsp10-16) is still scarce, we screened the active site for potential binding of drug-like and fragment-like compounds using X-ray crystallography. The screened set of 234 compounds consists of derivatives of the natural substrate S -adenosyl methionine (SAM) and adenine derivatives, of which some have been described previously as methyltransferase inhibitors and nsp16 binders. A docking study guided the selection of many of these compounds. Here we report structures of binders to the SAM site of nsp10-16 and for two of them, toyocamycin and sangivamycin, we present additional crystal structures in the presence of a second substrate, Cap0-analog/Cap0-RNA. The identified hits were tested for binding to nsp10-16 in solution and antiviral activity in cell culture. Our data provide important structural information on various molecules that bind to the SAM substrate site which can be used as novel starting points for selective methyltransferase inhibitor designs.

show abstract

SiteMine: Large‐scale binding site similarity searching in protein structure databases

Cited by 4 publications

References 71 publications

Database-Driven Identification of Structurally Similar Protein-Protein Interfaces

Database-Driven Identification of Structurally Similar Protein-Protein Interfaces

SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery

SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery

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