scholarly journals Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein–protein interaction

RSC Advances ◽  
2021 ◽  
Vol 11 (38) ◽  
pp. 23270-23279
Author(s):  
Qi Miao ◽  
Wanheng Zhang ◽  
Kuojun Zhang ◽  
He Li ◽  
Jidong Zhu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Interaction ◽  
Rational Design ◽  
Peptide Inhibitor ◽  
Protein Protein Interaction ◽  
Comparable Activity ◽  
L1 Protein ◽  
Macrocyclic Peptide

The co-crystal structure and CADD-guided rational design of JMPDP-027 which has comparable activity to mAb in both in vitro and in vivo tests.

scholarly journals Definition of a minimal munc18c domain that interacts with syntaxin 4

2000 ◽  
Vol 350 (3) ◽  
pp. 741-746 ◽  
Author(s):  
Julian GRUSOVIN ◽  
Violet STOICHEVSKA ◽  
Keith H. GOUGH ◽  
Katrina NUNAN ◽  
Colin W. WARD ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Full Length ◽  
Yeast Two Hybrid ◽  
Protein Protein Interaction ◽  
Interaction Studies ◽  
Syntaxin 4 ◽  
Definition Of ◽  
Two Hybrid

munc18c is a critical protein involved in trafficking events associated with syntaxin 4 and which also mediates inhibitory effects on vesicle docking and/or fusion. To investigate the domains of munc18c responsible for its interaction with syntaxin 4, fragments of munc18c were generated and their interaction with syntaxin 4 examined in vivo by the yeast two-hybrid assay. In vitro protein–protein interaction studies were then used to confirm that the interaction between the proteins was direct. Full-length munc18c1–592, munc18c1–139 and munc18c1–225, but not munc18c226–592, munc18c1–100, munc18c43–139 or munc18c66–139, interacted with the cytoplasmic portion of syntaxin 4, Stx42–273, as assessed by yeast two-hybrid assay of growth on nutritionally deficient media and by β-galactosidase reporter induction. The N-terminal predicted helix-a-helix-b-helix-c region of syntaxin 4, Stx429–157, failed to interact with full-length munc18c1–592, indicating that a larger portion of syntaxin 4 is necessary for the interaction. The yeast two-hybrid results were confirmed by protein–protein interaction studies between Stx42–273 and glutathione S-transferase fusion proteins of munc18c. Full-length munc18c1–592, munc18c1–139 and munc18c1–225 interacted with Stx42–273 whereas munc18c1–100 did not, consistent with the yeast two-hybrid data. These data thus identify a region of munc18c between residues 1 and 139 as a minimal domain for its interaction with syntaxin 4.

Specificity of protein-RNA and protein-protein interaction upon assembly of TMV in vivo and in vitro

Virology ◽  
1975 ◽  
Vol 67 (1) ◽  
pp. 1-13 ◽  
Author(s):  
T.I. Atabekova ◽  
M.E. Taliansky ◽  
J.G. Atabekov
Keyword(s):  
Protein Interaction ◽  
Protein Protein Interaction

scholarly journals Evolutionary diversification of protein–protein interactions by interface add-ons

2017 ◽  
Vol 114 (40) ◽  
pp. E8333-E8342 ◽  
Author(s):  
Maximilian G. Plach ◽  
Florian Semmelmann ◽  
Florian Busch ◽  
Markus Busch ◽  
Leonhard Heizinger ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Evolutionary Strategy ◽  
Structural Level ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Evolutionary Diversification

Cells contain a multitude of protein complexes whose subunits interact with high specificity. However, the number of different protein folds and interface geometries found in nature is limited. This raises the question of how protein–protein interaction specificity is achieved on the structural level and how the formation of nonphysiological complexes is avoided. Here, we describe structural elements called interface add-ons that fulfill this function and elucidate their role for the diversification of protein–protein interactions during evolution. We identified interface add-ons in 10% of a representative set of bacterial, heteromeric protein complexes. The importance of interface add-ons for protein–protein interaction specificity is demonstrated by an exemplary experimental characterization of over 30 cognate and hybrid glutamine amidotransferase complexes in combination with comprehensive genetic profiling and protein design. Moreover, growth experiments showed that the lack of interface add-ons can lead to physiologically harmful cross-talk between essential biosynthetic pathways. In sum, our complementary in silico, in vitro, and in vivo analysis argues that interface add-ons are a practical and widespread evolutionary strategy to prevent the formation of nonphysiological complexes by specializing protein–protein interactions.

scholarly journals Protein-Protein Interaction Detection: Methods and Analysis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
V. Srinivasa Rao ◽  
K. Srinivas ◽  
G. N. Sujini ◽  
G. N. Sunand Kumar
Keyword(s):  
Protein Interaction ◽  
Protein Function ◽  
In Silico ◽  
Affinity Purification ◽  
Phylogenetic Profile ◽  
Detection Methods ◽  
Protein Protein Interaction ◽  
Interaction Detection

Protein-protein interaction plays key role in predicting the protein function of target protein and drug ability of molecules. The majority of genes and proteins realize resulting phenotype functions as a set of interactions. The in vitro and in vivo methods like affinity purification, Y2H (yeast 2 hybrid), TAP (tandem affinity purification), and so forth have their own limitations like cost, time, and so forth, and the resultant data sets are noisy and have more false positives to annotate the function of drug molecules. Thus, in silico methods which include sequence-based approaches, structure-based approaches, chromosome proximity, gene fusion, in silico 2 hybrid, phylogenetic tree, phylogenetic profile, and gene expression-based approaches were developed. Elucidation of protein interaction networks also contributes greatly to the analysis of signal transduction pathways. Recent developments have also led to the construction of networks having all the protein-protein interactions using computational methods for signaling pathways and protein complex identification in specific diseases.

scholarly journals Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2277 ◽  
Author(s):  
Lei Wang ◽  
Lixiao Zhang ◽  
Li Li ◽  
Jingsheng Jiang ◽  
Zhen Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitor ◽  
Protein Protein Interaction ◽  
Molecule Inhibitor ◽  
Dependent Cell ◽  
Hsp90 Chaperone

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu47, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.

Hypersensitive mousetraps, α1-antitrypsin deficiency and dementia

2002 ◽  
Vol 30 (2) ◽  
pp. 89-92 ◽  
Author(s):  
D. A. Lomas ◽  
A. Lourbakos ◽  
S.-A. Cumming ◽  
D. Belorgey
Keyword(s):  
Protein Interaction ◽  
Inclusion Bodies ◽  
Serine Proteinase ◽  
Specific Protein ◽  
Structural Basis ◽  
Protein Protein Interaction ◽  
Antitrypsin Deficiency ◽  
Familial Encephalopathy

α1-Antitrypsin functions as a ‘mousetrap’ to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu342 → Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and β-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z α1-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and α1-anti-chymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.

scholarly journals Adenovirus Transforming Protein E1A Induces c-Myc in Quiescent Cells by a Novel Mechanism

2009 ◽  
Vol 83 (10) ◽  
pp. 4810-4822 ◽  
Author(s):  
Ravi-Kumar Kadeppagari ◽  
Natesan Sankar ◽  
Bayar Thimmapaya
Keyword(s):  
Binding Site ◽  
Protein Interaction ◽  
Cell Transformation ◽  
Viral Oncoprotein ◽  
Protein Protein Interaction ◽  
Quiescent Cells ◽  
Tumor Viruses ◽  
Transcription Factor Yy1

ABSTRACT Previously we showed that the E1A binding proteins p300 and CBP negatively regulate c-Myc in quiescent cells and that binding of E1A to p300 results in the induction of c-Myc and thereby induction of S phase. We demonstrated that p300 and HDAC3 cooperate with the transcription factor YY1 at an upstream YY1 binding site and repress the Myc promoter. Here we show that the small E1A protein induces c-Myc by interfering with the protein-protein interaction between p300, YY1, and HDAC3. Wild-type E1A but not the E1A mutants that do not bind to p300 interfered in recruitment of YY1, p300, and HDAC3 to the YY1 binding site. As E1A started to accumulate after infection, it transiently associated with promoter-bound p300. Subsequently, YY1, p300, and HDAC3 began to dissociate from the promoter. Later in infection, E1A dissociated from the promoter as well as p300, YY1, and HDAC3. Removal of HDAC3 from the promoter correlated with increased acetylation of Myc chromatin and induction. In vivo E1A stably associated with p300 and dissociated YY1 and HDAC3 from the trimolecular complex. In vitro protein-protein interaction studies indicated that E1A initially binds to the p300-YY1-HDAC3 complex, briefly associates with it, and then dissociates the complex, recapitulating somewhat the in vivo situation. Thus, E1A binding to the C-terminal region of p300 disrupts the important corepressor function provided by p300 in repressing c-Myc. Our results reveal a novel mechanism by which a viral oncoprotein activates c-Myc in quiescent cells and raise the possibility that the oncoproteins encoded by the small-DNA tumor viruses may use this mechanism to induce c-Myc, which may be critical for cell transformation.

scholarly journals An H3K9 methylation-dependent protein interaction regulates the non-enzymatic functions of a putative histone demethylase

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Gulzhan Raiymbek ◽  
Sojin An ◽  
Nidhi Khurana ◽  
Saarang Gopinath ◽  
Ajay Larkin ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Histone Demethylase ◽  
H3k9 Methylation ◽  
Heterochromatin Formation ◽  
Protein Protein Interaction ◽  
Enzymatic Function ◽  
C Terminus ◽  
Jmjc Domain

H3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that reverses epigenetic silencing. Here, we reveal an inversion of this paradigm where a putative histone demethylase Epe1 in fission yeast, has a non-enzymatic function that opposes heterochromatin assembly. Mutations within the putative catalytic JmjC domain of Epe1 disrupt its interaction with Swi6HP1 suggesting that this domain might have other functions besides enzymatic activity. The C-terminus of Epe1 directly interacts with Swi6HP1, and H3K9 methylation stimulates this protein-protein interaction in vitro and in vivo. Expressing the Epe1 C-terminus is sufficient to disrupt heterochromatin by outcompeting the histone deacetylase, Clr3 from sites of heterochromatin formation. Our results underscore how histone modifying proteins that resemble enzymes have non-catalytic functions that regulate the assembly of epigenetic complexes in cells.

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