scholarly journals SpeciFlex: A Protocol for Mining Binding Site Conformational Selectivity in Structure-Based Inhibitor Discovery

2018 ◽  
Author(s):  
Matthew E. Tonero ◽  
Leslie A. Kuhn
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Yersinia Pestis ◽  
Target Site ◽  
Population Differences ◽  
Homologous Proteins ◽  
Conformational Ensembles ◽  
Conformational Population ◽  
Inhibitor Discovery ◽  
Homologous Site

AbstractSelectivity for a target site is challenging when the site is conserved in homologous proteins. A novel protocol is presented for attaining selectivity by taking advantage of conformational population differences between homologs. Conformational ensembles of the targeted protein and the homolog are compared to identify pockets significantly populated in the target, but rarely or never sampled in the homolog. SLIDE screening then identifies molecules that fit the unique pocket and also interact well with an adjacent substrate pocket. The SpeciFlex protocol, demonstrated for a pair of pyrophosphokinases, yields ligand candidates with good interactions in both the substrate and unique pockets of the target Yersinia pestis protein, while selecting against interactions with the homologous site in Escherichia coli.

scholarly journals Analysis of the puromycin binding site in the 70 S ribosome of Escherichia coli at the peptide level

1994 ◽  
Vol 269 (28) ◽  
pp. 18315-18319
Author(s):  
O. Bischof ◽  
V. Kruft ◽  
B. Wittmann-Liebold
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Peptide Level

scholarly journals Excision and transposition of Tn5 as an SOS activity in Escherichia coli.

Genetics ◽  
1991 ◽  
Vol 128 (1) ◽  
pp. 45-57 ◽  
Author(s):  
C T Kuan ◽  
S K Liu ◽  
I Tessman
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Reca Protein ◽  
Precursor Molecule ◽  
Functional Integrity ◽  
Lexa Protein ◽  
Lexa Binding ◽  
Additional Role ◽  
Stimulation Of

Abstract Excision and transposition of the Tn5 element in Escherichia coli ordinarily appear to occur by recA-independent mechanisms. However, recA(Prtc) genes, which encode RecA proteins that are constitutively activated to the protease state, greatly enhanced excision and transposition; both events appeared to occur concomitantly and without destruction of the donor DNA. The recombinase function of the RecA protein was not required. Transposition was accompanied by partial, and occasionally full, restoration of the functional integrity of the gene vacated by the excised Tn5. The stimulation of transposition was inhibited by an uncleavable LexA protein and was strongly enhanced by an additional role of the RecA(Prtc) protein besides its mediation of LexA cleavage. To account for the enhanced transposition, we suggest that (i) there may be a LexA binding site within the promoter for the IS50 transposase, (ii) activated RecA may cleave the IS50 transposition inhibitor, and (iii) the transposase may be formed by RecA cleavage of a precursor molecule.

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