Analysis of protein-protein interactions and the effects of amino acid mutations on their energetics. The importance of water molecules in the binding epitope

1997 ◽  
Vol 269 (2) ◽  
pp. 281-297 ◽  
Author(s):  
D.G. Covell ◽  
A. Wallqvist
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Water Molecules ◽  
Protein Protein Interactions ◽  
Binding Epitope ◽  
Amino Acid Mutations

Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer

2019 ◽  
Vol 19 (6) ◽  
pp. 457-466 ◽  
Author(s):  
V. Kanakaveti ◽  
P. Anoosha ◽  
R. Sakthivel ◽  
S.K. Rayala ◽  
M.M. Gromiha
Keyword(s):  
Amino Acid ◽  
Small Molecules ◽  
Protein Interactions ◽  
Chemical Space ◽  
Clinical Success ◽  
Growth Factor Receptor ◽  
Protein Protein Interactions ◽  
Functional Aspects ◽  
Amino Acid Mutations ◽  
Targeted Inhibition

Background:Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects.Objective:In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer.Methods:Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs.Results:The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges.Conclusion:Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.

scholarly journals SAAMBE-3D: Predicting Effect of Mutations on Protein–Protein Interactions

2020 ◽  
Vol 21 (7) ◽  
pp. 2563 ◽  
Author(s):  
Swagata Pahari ◽  
Gen Li ◽  
Adithya Krishna Murthy ◽  
Siqi Liang ◽  
Robert Fragoza ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Pearson Correlation ◽  
Normal Function ◽  
Protein Protein Interactions ◽  
Cornell University ◽  
Genome Wide ◽  
New Development ◽  
Amino Acid Mutations

Maintaining wild type protein–protein interactions is essential for the normal function of cell and any mutation that alter their characteristics can cause disease. Therefore, the ability to correctly and quickly predict the effect of amino acid mutations is crucial for understanding disease effects and to be able to carry out genome-wide studies. Here, we report a new development of the SAAMBE method, SAAMBE-3D, which is a machine learning-based approach, resulting in accurate predictions and is extremely fast. It achieves the Pearson correlation coefficient ranging from 0.78 to 0.82 depending on the training protocol in benchmarking five-fold validation test against the SKEMPI v2.0 database and outperforms currently existing algorithms on various blind-tests. Furthermore, optimized and tested via five-fold cross-validation on the Cornell University dataset, the SAAMBE-3D achieves AUC of 1.0 and 0.96 on a homo and hereto-dimer test datasets. Another important feature of SAAMBE-3D is that it is very fast, it takes less than a fraction of a second to complete a prediction. SAAMBE-3D is available as a web server and as well as a stand-alone code, the last one being another important feature allowing other researchers to directly download the code and run it on their local computer. Combined all together, SAAMBE-3D is an accurate and fast software applicable for genome-wide studies to assess the effect of amino acid mutations on protein–protein interactions. The webserver and the stand-alone codes (SAAMBE-3D for predicting the change of binding free energy and SAAMBE-3D-DN for predicting if the mutation is disruptive or non-disruptive) are available.

scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

Engineering an acetyllysine reader with photocrosslinking amino acid for interactome profiling

2021 ◽  
Author(s):  
Babu Sudhamalla ◽  
Anirban Roy ◽  
Soumen Barman ◽  
Jyotirmayee Padhan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Protein Interactions ◽  
Site Specific ◽  
Powerful Approach

The site-specific installation of light-activable crosslinker unnatural amino acids offers a powerful approach to trap transient protein-protein interactions both in vitro and in vivo. Herein, we engineer a bromodomain to...

scholarly journals Engineering bromodomains with a photoactive amino acid by engaging ‘Privileged’ tRNA synthetases

2020 ◽  
Vol 56 (25) ◽  
pp. 3641-3644
Author(s):  
Shana Wagner ◽  
Babu Sudhamalla ◽  
Philip Mannes ◽  
Sushma Sappa ◽  
Sam Kavoosi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chemical Synthesis ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Site Specific ◽  
Trna Synthetases

An improved chemical synthesis, site-specific incorporation and enhanced photo-crosslinking ability of tmdF have been demonstrated in the context of protein–protein interactions.

scholarly journals Single Amino Acid Replacements in RocA Disrupt Protein-Protein Interactions To Alter the Molecular Pathogenesis of Group A Streptococcus

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Paul E. Bernard ◽  
Amey Duarte ◽  
Mikhail Bogdanov ◽  
James M. Musser ◽  
Randall J. Olsen
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Molecular Pathogenesis ◽  
Single Amino Acid ◽  
Accessory Protein ◽  
Protein Protein Interactions ◽  
Tissue Destruction ◽  
Intact Cells ◽  
Group A

ABSTRACT Group A Streptococcus (GAS) is a human-specific pathogen and major cause of disease worldwide. The molecular pathogenesis of GAS, like many pathogens, is dependent on the coordinated expression of genes encoding different virulence factors. The control of virulence regulator/sensor (CovRS) two-component system is a major virulence regulator of GAS that has been extensively studied. More recent investigations have also involved regulator of Cov (RocA), a regulatory accessory protein to CovRS. RocA interacts, in some manner, with CovRS; however, the precise molecular mechanism is unknown. Here, we demonstrate that RocA is a membrane protein containing seven transmembrane helices with an extracytoplasmically located N terminus and cytoplasmically located C terminus. For the first time, we demonstrate that RocA directly interacts with itself (RocA) and CovS, but not CovR, in intact cells. Single amino acid replacements along the entire length of RocA disrupt RocA-RocA and RocA-CovS interactions to significantly alter the GAS virulence phenotype as defined by secreted virulence factor activity in vitro and tissue destruction and mortality in vivo. In summary, we show that single amino acid replacements in a regulatory accessory protein can affect protein-protein interactions to significantly alter the virulence of a major human pathogen.

Regulative interactions of the osmosensing C-terminal domain in the trimeric glycine betaine transporter BetP from Corynebacterium glutamicum

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Reinhard Krämer ◽  
Christine Ziegler
Keyword(s):  
Amino Acid ◽  
Corynebacterium Glutamicum ◽  
Protein Interactions ◽  
Regulation Mechanism ◽  
Protein Protein Interactions ◽  
Molecular Switching ◽  
X Ray ◽  
X Ray Crystallography ◽  
Terminal Domain ◽  
Domain Reorientation

Abstract Activation of the osmoregulated trimeric betaine transporter BetP from Corynebacterium glutamicum was shown to depend mainly on the correct folding and integrity of its 55 amino acid long, partly α-helical C-terminal domain. Reorientation of the three C-terminal domains in the BetP trimer indicates different lipid-protein and protein-protein interactions of the C-terminal domain during osmoregulation. A regulation mechanism is suggested where this domain switches the transporter from the inactive to the active state. Interpretation of recently obtained electron and X-ray crystallography data of BetP led to a structure-function based model of C-terminal molecular switching involved in osmoregulation.

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