scholarly journals Structural Differences between the Avian and Human H7N9 Hemagglutinin Proteins Are Attributable to Modifications in Salt Bridge Formation: A Computational Study with Implications in Viral Evolution

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e76764 ◽  
Author(s):  
Marni E. Cueno ◽  
Kenichi Imai ◽  
Muneaki Tamura ◽  
Kuniyasu Ochiai
Keyword(s):  
Computational Study ◽  
Viral Evolution ◽  
Salt Bridge ◽  
Bridge Formation ◽  
Structural Differences

scholarly journals Rational design of new NO and redox sensitivity into connexin26 hemichannels

Open Biology ◽  
2015 ◽  
Vol 5 (2) ◽  
pp. 140208 ◽  
Author(s):  
Louise Meigh ◽  
Daniel Cook ◽  
Jie Zhang ◽  
Nicholas Dale
Keyword(s):  
Redox Potential ◽  
Rational Design ◽  
Salt Bridge ◽  
Disulfide Bridge ◽  
Wild Type ◽  
No Donors ◽  
Bridge Formation ◽  
Redox Sensitivity ◽  
Intracellular Redox

CO 2 directly opens hemichannels of connexin26 (Cx26) by carbamylating K125, thereby allowing salt bridge formation with R104 of the neighbouring subunit in the connexin hexamer. The formation of the inter-subunit carbamate bridges within the hexameric hemichannel traps it in the open state. Here, we use insights derived from this model to test whether the range of agonists capable of opening Cx26 can be extended by promoting the formation of analogous inter-subunit bridges via different mechanisms. The mutation K125C gives potential for nitrosylation on Cys125 and formation of an SNO bridge to R104 of the neighbouring subunit. Unlike wild-type Cx26 hemichannels, which are insensitive to NO and NO 2 − , hemichannels comprising Cx26 K125C can be opened by NO 2 − and NO donors. However, NO 2 − was unable to modulate the doubly mutated (K125C, R104A) hemichannels, indicating that an inter-subunit bridge between C125 and R104 is required for the opening action of NO 2 − . In a further test, we introduced two mutations into Cx26, K125C and R104C, to allow disulfide bridge formation across the inter-subunit boundary. These doubly mutated hemichannels open in response to changes in intracellular redox potential.

Molecular basis for defective secretion of the Z variant of human alpha-1-proteinase inhibitor: secretion of variants having altered potential for salt bridge formation between amino acids 290 and 342

1989 ◽  
Vol 9 (4) ◽  
pp. 1406-1414
Author(s):  
A A McCracken ◽  
K B Kruse ◽  
J L Brown
Keyword(s):  
Amino Acid ◽  
Proteinase Inhibitor ◽  
Conformational Stability ◽  
Point Mutations ◽  
Salt Bridge ◽  
Site Directed Mutagenesis ◽  
Wild Type ◽  
Functional Importance ◽  
Bridge Formation ◽  
Cos Cells

Human alpha-1-proteinase inhibitor (A1PI) deficiency, associated with the Z-variant A1PI (A1PI/Z) gene, results from defective secretion of the inhibitor from the liver. The A1PI/Z gene exhibits two point mutations which specify amino acid substitutions, Val-213 to Ala and Glu-342 to Lys. The functional importance of these substitutions in A1PI deficiency was investigated by studying the secretion of A1PI synthesized in COS cells transfected with A1PI genes altered by site-directed mutagenesis. This model system correctly duplicates the secretion defect seen in individuals homozygous for the A1PI/Z allele and shows that the substitution of Lys for Glu-342 alone causes defective secretion of A1PI. The substitution of Lys for Glu-342 eliminates the possibility for a salt bridge between residues 342 and 290, which may decrease the conformational stability of the molecule and thus account for the secretion defect. However, when we removed the potential to form a salt bridge from the wild-type inhibitor by changing Lys-290 to Glu (A1PI/SB-290Glu), secretion was not reduced to the 19% of normal level seen for A1PI/Z-342Lys; in fact, 75% of normal secretion was observed. When the potential for salt bridge formation was returned to A1PI/Z-342Lys by changing Lys-290 to Glu, only 46% of normal secretion was seen. These data indicate that the amino acid substitution at position 342, rather than the potential to form the 290-342 salt bridge, is the critical alteration leading to the defect in A1PI secretion.

Specificity profiling of human trypsin-isoenzymes

2018 ◽  
Vol 399 (9) ◽  
pp. 997-1007 ◽  
Author(s):  
Oliver Schilling ◽  
Martin L. Biniossek ◽  
Bettina Mayer ◽  
Brigitta Elsässer ◽  
Hans Brandstetter ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Aspartic Acid ◽  
Therapeutic Target ◽  
Cleavage Site ◽  
Quantitative Proteomics ◽  
Salt Bridge ◽  
Peptide Libraries ◽  
Peptide Substrates ◽  
Bridge Formation ◽  
Specific Inhibitors

AbstractIn humans, three different trypsin-isoenzymes have been described. Of these, trypsin-3 appears to be functionally different from the others. In order to systematically study the specificity of the trypsin-isoenzymes, we utilized proteome-derived peptide libraries and quantitative proteomics. We found similar specificity profiles dominated by the well-characterized preference for cleavage after lysine and arginine. Especially, trypsin-1 slightly favored lysine over arginine in this position, while trypsin-3 did not discriminate between them. In the P1′ position, which is the residue C-terminal to the cleavage site, we noticed a subtle enrichment of alanine and glycine for all three trypsins and for trypsin-3 there were additional minor P1′ and P2′ preferences for threonine and aspartic acid, respectively. These findings were confirmed by FRET peptide substrates showing different susceptibility to cleavage by different trypsins. The preference of trypsin-3 for aspartic acid in P2′ is explained by salt bridge formation with the unique Arg193. This salt bridge enables and stabilizes a canonical oxyanion conformation by the amides of Ser195 and Arg193, thus manifesting a selective substrate-assisted catalysis. As trypsin-3 has been proposed to be a therapeutic target and marker for cancers, our results may aid the development of specific inhibitors for cancer therapy and diagnostic probes.

scholarly journals Understanding the impacts of self-shuffling approach on structure and function of shuffled endoglucanase enzyme via MD simulations

2020 ◽  
Vol 45 (2) ◽  
Author(s):  
Aslı Yenenler ◽  
Umut Gerlevik ◽  
Ugur Sezerman
Keyword(s):  
Experimental Studies ◽  
Salt Bridge ◽  
Md Simulations ◽  
Structure And Function ◽  
Computational Approach ◽  
Intramolecular Interactions ◽  
Structural Basis ◽  
Functional Differences ◽  
Structural Differences ◽  
And Function

AbstractObjectiveWe identify the impacts of structural differences on functionality of EG3_S2 endoglucanase enzyme with MD studies. The results of previous experimental studies have been explained in details with computational approach. The objective of this study is to explain the functional differences between shuffled enzyme (EG3_S2) and its native counterpart (EG3_nat) from Trichoderma reseei, via Molecular Dynamics approach.Materials and methodsFor this purpose, we performed MD simulations along 30 ns at three different reaction temperatures collected as NpT ensemble, and then monitored the backbone motion, flexibilities of residues, and intramolecular interactions of EG3_S2 and EG3_nat enzymes.ResultsAccording to MD results, we conclude that EG3_S2 and EG3_nat enzymes have unique RMSD patterns, e.g. RMSD pattern of EG3_S2 is more dynamic than that of EG3_nat at all temperatures. In addition to this dynamicity, EG3_S2 establishes more salt bridge interactions than EG3_nat.ConclusionBy taking these results into an account with the preservation of catalytic Glu residues in a proper manner, we explain the structural basis of differences between shuffled and native enzyme via molecular dynamic studies.

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