scholarly journals Differential modulation of transcriptional activity of oestrogen receptors by direct protein–protein interactions with retinoid receptors

1998 ◽  
Vol 336 (3) ◽  
pp. 711-717 ◽  
Author(s):  
Mi-Ryoung SONG ◽  
Soo-Kyung LEE ◽  
Young-Woo SEO ◽  
Hueng-Sik CHOI ◽  
Jae Woon LEE ◽  
...  
Keyword(s):  
Cross Talk ◽  
Protein Interactions ◽  
Oestrogen Receptors ◽  
Differential Modulation ◽  
Protein Protein Interactions ◽  
Glutathione S Transferase ◽  
Retinoid Receptors ◽  
Binding Domains ◽  
X Receptors

Control of oestradiol-responsive gene regulation by oestrogen receptors (ERs) may involve complex cross-talk with retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Recently, we have shown that ERα directly interacts with RARα and RXRα through their ligand binding domains (LBDs). In the present work, we extend these results by showing that ERβ binds similarly to RARα and RXRα but not to the glucocorticoid receptor, as demonstrated by the yeast two-hybrid tests and glutathione S-transferase pull-down assays. These direct interactions were also demonstrated in gel-shift assays, in which the oestrogen response element (ERE) binding by ERα was enhanced by the RXRα LBD but was abolished by the RARα LBD. In addition, we showed that RARα and RXRα bound the ERE as efficiently as ERα, suggesting that competition for DNA binding may affect the transactivation function of the ER. In transient transfection experiments, co-expression of RARα or RXRα, along with ERα or ERβ, revealed differential modulation of the ERE-dependent transactivation, which was distinct from the results when each receptor alone was co-transfected. Importantly, when the LBD of RARα was co-expressed with ERα, transactivation of ERα on the ERE was repressed as efficiently as when wild-type RARα was co-expressed. Furthermore, liganded RARα or unliganded RXRα enhanced the ERα transactivation, suggesting the formation of transcriptionally active heterodimer complexes between the ER and retinoid receptors. Taken together, these results suggest that direct protein–protein interactions may play major roles in the determination of the biological consequences of cross-talk between ERs and RARα or RXRα.

scholarly journals Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Avital Shushan ◽  
Mickey Kosloff
Keyword(s):  
Protein Interactions ◽  
Structural Elements ◽  
Protein Protein Interactions ◽  
Immunity Protein ◽  
Rational Engineering ◽  
High Affinity ◽  
Comparative Structure ◽  
Polar Interactions ◽  
Exquisite Specificity

AbstractThe interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity and specificity is still lacking. Here, we used comparative structure-based energy calculations to map residues that substantially contribute to interactions across native and engineered complexes of colicins/pyocins and immunity proteins. We show that the immunity protein α1–α2 motif is a unique structurally-dissimilar element that restricts interaction specificity towards all colicins/pyocins, in both engineered and native complexes. This motif combines with a diverse and extensive array of electrostatic/polar interactions that enable the exquisite specificity that characterizes these interactions while achieving ultra-high affinity. Surprisingly, the divergence of these contributing colicin residues is reciprocal to residue conservation in immunity proteins. The structurally-dissimilar immunity protein α1–α2 motif is recognized by divergent colicins similarly, while the conserved immunity protein α3 helix interacts with diverse colicin residues. Electrostatics thus plays a key role in setting interaction specificity across all colicins and immunity proteins. Our analysis and resulting residue-level maps illuminate the molecular basis for these protein–protein interactions, with implications for drug development and rational engineering of these interfaces.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

Determination of Protein–Protein Interactions in a Mixture of Two Monoclonal Antibodies

2019 ◽  
Vol 16 (12) ◽  
pp. 4775-4786 ◽  
Author(s):  
Priyanka Singh ◽  
Aisling Roche ◽  
Christopher F. van der Walle ◽  
Shahid Uddin ◽  
Jiali Du ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Protein Interactions ◽  
Protein Protein Interactions

Address of the President Lord Todd at the anniversary meeting, 30 November 1976

1977 ◽  
Vol 352 (1671) ◽  
pp. 451-462
Keyword(s):  
Protein Interactions ◽  
Complex Analysis ◽  
Organic Molecules ◽  
Heavy Atom ◽  
Vitamin B ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Polypeptide Chains ◽  
Complex Organic

The Copley Medal is awarded to Professor Dorothy M. C. Hodgkin, O. M., F. R. S. Professor Dorothy Hodgkin is distinguished for her research on the structure of complex organic molecules by the method of X-ray crystallography. She was among the first to appreciate the importance of heavy-atom phase-determining methods and these she used to effect the first complete determination of the stereochemistry of a sterol derivative in her analysis of cholesteryl iodide. The same powerful method of analysis and in particular her extraordinary gift of being able to interpret correctly the complex, partially resolved and often misleading electron density patterns that are first obtained, have been responsible for her success in elucidating the structures of many other important natural products, especially penicillin and vitamin B 12 . This last is by far the most beautiful and complex analysis which has yet been completed in this field and it is of fundamental importance to chemical science. In recent years Professor Hodgkin’s main interest has been devoted to the structure of insulin, on which she has been working on and off since 1935. Carried out with characteristic precision, this work has become a mine of stereochemical information relating to contacts between polypeptide chains and is of great significance for our interpretation of protein-protein interactions.

NMR for the design of functional mimetics of protein-protein interactions: one key is in the building of bridges

1998 ◽  
Vol 76 (2-3) ◽  
pp. 177-188 ◽  
Author(s):  
Jianxing Song ◽  
Feng Ni
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Experimental Approach ◽  
Structural Information ◽  
Peptide Ligands ◽  
Protein Protein Interactions ◽  
Binding Residues ◽  
Related Proteins ◽  
Binding Inhibitors

Using the design of bivalent and bridge-binding inhibitors of thrombin as an example, we review an NMR-based experimental approach for the design of functional mimetics of protein-protein interactions. The strategy includes: (i) identification of binding residues in peptide ligands by differential resonance perturbation, (ii) determination of protein-bound structures of peptide ligands by use of transferred NOEs, (iii) minimization of larger protein and peptide ligands on the basis of NMR structural information, and (iv) linkage of two weakly binding mimetics to produce an inhibitor with enhanced affinity and specificity. This approach can be especially effective for the design of potent and selective functional mimetics of protein-protein interactions because it is less likely that the surfaces of two related proteins or enzymes share two identical binding sites or regions.Key words: NMR, protein-protein interactions, functional mimetics, bridge-binding inhibitors, thrombin.

scholarly journals Insulin signalling: putting the G- in protein-protein interactions

2004 ◽  
Vol 380 (1) ◽  
pp. e11-e12 ◽  
Author(s):  
Craig C. MALBON
Keyword(s):  
Insulin Receptor ◽  
Cross Talk ◽  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Cell Biology ◽  
Receptor Tyrosine Kinases ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Protein Interactions ◽  
Proximal Point

Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and via heterotrimeric G-proteins, such as Gαi, Gαs and Gαq family members, constitute two of most avidly studied paradigms in cell biology. That elements of these two populous signalling pathways must cross-talk to achieve proper signalling in the regulation of cell proliferation, differentiation and metabolism has been anticipated, but the evolution of our thinking and the analysis of such cross-talk have lagged behind the ever-expanding troupe of players and the recognition of multivalency as the rule, rather than the exception, in signalling biology. New insights have been provided by Kreuzer et al. in this issue of the Biochemical Journal, in which insulin is shown to provoke recruitment of Gαi-proteins to insulin-receptor-based complexes that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a proximal point in the insulin-sensitive cascade of signalling. Understanding the convergence and cross-talk of signals from the receptor tyrosine kinases and G-protein-coupled receptor pathways in physical, spatial and temporal contexts will remain a major challenge of cell biology.

Determination of Protein-Protein Interactions of ICln by the Yeast Two-Hybrid System

2001 ◽  
Vol 11 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Andreas Schmarda ◽  
Friedrich Fresser ◽  
Martin Gschwentner ◽  
Johannes Fürst ◽  
Markus Ritter ◽  
...  
Keyword(s):  
Hybrid System ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Yeast Two Hybrid ◽  
Yeast Two Hybrid System ◽  
Two Hybrid

scholarly journals Structural Classification of Bacterial Response Regulators: Diversity of Output Domains and Domain Combinations

2006 ◽  
Vol 188 (12) ◽  
pp. 4169-4182 ◽  
Author(s):  
Michael Y. Galperin
Keyword(s):  
Protein Interactions ◽  
Rna Binding ◽  
Transcriptional Regulators ◽  
Bacterial Cells ◽  
Protein Protein Interactions ◽  
Response Regulators ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Archaeal Species

ABSTRACT CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. In this work, 4,610 response regulators, encoded in complete genomes of 200 bacterial and archaeal species, were identified and classified by their domain architectures. Previously uncharacterized output domains were analyzed and, in some cases, assigned to known domain families. Transcriptional regulators of the OmpR, NarL, and NtrC families were found to comprise almost 60% of all response regulators; transcriptional regulators with other DNA-binding domains (LytTR, AraC, Spo0A, Fis, YcbB, RpoE, and MerR) account for an additional 6%. The remaining one-third is represented by the stand-alone REC domain (∼14%) and its combinations with a variety of enzymatic (GGDEF, EAL, HD-GYP, CheB, CheC, PP2C, and HisK), RNA-binding (ANTAR and CsrA), protein- or ligand-binding (PAS, GAF, TPR, CAP_ED, and HPt) domains, or newly described domains of unknown function. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription, enzyme activity, and/or protein-protein interactions in response to environmental challenges. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online at http://www.ncbi.nlm.nih.gov/Complete_Genomes/RRcensus.html .

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