ConSurf: Using Evolutionary Data to Raise Testable Hypotheses about Protein Function

Celniker, Gershon; Nimrod, Guy; Ashkenazy, Haim; Glaser, Fabian; Martz, Eric; Mayrose, Itay; Pupko, Tal; Ben‐Tal, Nir

doi:10.1002/ijch.201200096

Cited by 489 publications

(415 citation statements)

References 49 publications

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“…ConSurf analysis (28) shows that 39 residues display more than 96% conservation among sequences with Ͼ25% sequence identity to SeHisA. This conservation was mapped on a structure-based sequence alignment of sequences from previously characterized HisA and PriA enzymes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Two-step Ligand Binding in a (βα)8 Barrel Enzyme

Söderholm

Guo

Newton

et al. 2015

Journal of Biological Chemistry

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Background: HisA catalyzes a ring-opening isomerization reaction in histidine biosynthesis. Results: Catalytic residues and conformational changes upon substrate binding are clarified by structures, kinetics, and mutagenesis. Conclusion: Closing of active site loops in HisA brings the substrate into a product-like conformation before catalysis. Significance: This exemplifies coupled conformational changes in a (␤␣) 8 barrel enzyme and its substrate and clarifies the mechanistic cycle of HisA.

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Section: Resultsmentioning

confidence: 99%

Two-step Ligand Binding in a (βα)8 Barrel Enzyme

Söderholm

Guo

Newton

et al. 2015

Journal of Biological Chemistry

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“…MSA files were handled using JalView software [61]. Homolog-based model and multiple alignment were used for sequence conservation illustration with the CONSURF server (http://consurf.tau.ac.il/) [62]. …”

Section: Kti12 Secondary Structure Predictions and Alignments With Elmentioning

confidence: 99%

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

Schaffrath¹,

Mehlgarten²,

Prochaska³

et al. 2017

Preprint

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Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex fromKluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin's action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein. From a kti12 mutant pool of zymocin survivors, we identify motifs in Kti12 that are functionally directly coupled to Elongator activity. In addition, shared requirement of U34 modifications for nonsense and missense tRNA suppression (SUP4; SOE1) strongly suggests that Kti12 and Elongator cooperate to assure proper tRNA functioning. We show that the Kti12 motifs are conserved in plant ortholog DRL1/ELO4 from Arabidopsis thaliana and seem to be involved in binding of cofactors (e.g. nucleotides, calmodulin). Elongator interaction defects triggered by mutations in these motifs correlate with phenotypes typical for loss of U34 modification. Thus, tRNA modification by Elongator appears to require physical contact with Kti12, and our preliminary data suggest that metabolic signals may affect proper communication between them.

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“…We then processed these alignments using a structural conservation analysis program, ConSurf, to generate relative conservation scores for each residue in the K-Ras sequence (23)(24)(25)(26). This algorithm calculates relative conservation scores for each residue that are then normalized so that the average score across all residues is zero.…”

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confidence: 99%

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

Hunter¹,

Gurbani²,

Ficarro

et al. 2014

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

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183

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Significance SML-8-73-1 (SML) is the first example, to our knowledge, of a GTP-competitive inhibitor of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras). A high-resolution structure of K-Ras G12C bound to SML shows K-Ras in an inactive conformation. In situ proteomic-based chemical profiling of SML demonstrates that SML is highly selective for K-Ras G12C over other small GTPases. A novel chemosensor-based assay allows measurement of covalent reaction rates between K-Ras G12C and SML and enables characterization of this reaction in the context of millimolar concentrations of GTP and GDP, well in exccss of what is found in living cells. These results demonstrate that even in the presence of high concentrations of GTP and GDP, SML is able to exchange into the GN site.

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ConSurf: Using Evolutionary Data to Raise Testable Hypotheses about Protein Function

Cited by 489 publications

References 49 publications

Two-step Ligand Binding in a (βα)8 Barrel Enzyme

Two-step Ligand Binding in a (βα)8 Barrel Enzyme

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

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