RESUMO
Renalase (RNLS) is a secretory protein discovered in 2005. It plays an important role in the regulation of blood pressure. Studies by two independent laboratories have shown that administration of purified recombinant RNLS reduced blood pressure in experimental animals. However, the mechanisms of the antihypertensive effect of RNLS still remain unclear, especially in the context of the shift in the catalytic paradigm of this protein. In addition, there is growing evidence that endogenous plasma/serum RNLS, detected by enzyme immunoassay, is not an intact protein secreted into the extracellular space, and exogenous recombinant RNLS is effectively cleaved during short-term incubation with human plasma samples. This suggests that the antihypertensive effect of RNLS may be due to peptides formed during proteolytic processing. Based on the results of a bioinformatics analysis of potential RNLS cleavage sites (Fedchenko et al., Medical Hypotheses, 2022; DOI: 10.1016/j.mehy.2022.110895), a number of short peptides have been identified in the RNLS sequence that show similarity to fragments of known peptide inhibitors of angiotensin-converting enzyme. Some of them were found as a part of larger RNLS peptides, formed during RNLS cleavage by chymotrypsin and, and to a lesser extent, by trypsin.
Assuntos
Anti-Hipertensivos , Monoaminoxidase , Humanos , Sequência de Aminoácidos , Fragmentos de Peptídeos , PeptídeosRESUMO
Interactions of cytochrome P450 2C9 (CYP2C9) were studied with the antitumor drug abiraterone and its pharmacologically active metabolite D4A, promising as an agent for prostate cancer treatment. It was shown by absorption spectroscopy, that both investigated compounds induced spectral changes of CYP2C9, indicating interactions of the pyridine nitrogen atom with the heme iron ion of the active site of the enzyme, but interactions of the ligands with the enzyme could be mediated by a water molecule bound to the heme iron ion. Based on the spectral changes, the values of dissociation constants (KS) for complexes of abiraterone and D4A with CYP2C9 were calculated as 1.73±0.14 µM and 3.95±0.16 µM. Both compounds inhibited O-demethylase activity of CYP2C9 towards its substrate. At 100 µM concentration of naproxen the concentrations of abiraterone, D4A and sulfaphenazole inhibiting CYP2C9 activity by 50% (IC50) were determined as 13.9 µM, 40 µM and 41 µM, respectively. The obtained results can be used for prognosis of drug-drug interactions at CYP2C9 level during administration of abiraterone or D4A as an antitumor agent for prostate cancer treatment in complex pharmacotherapy.
Assuntos
Neoplasias da Próstata , Androstenos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Heme , Humanos , Ferro , Masculino , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured in vitro at steady concentrations of the receptor and ligand, which are differed from in vivo environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness. This has increased attention in characterizing and predicting the rate constants of association and dissociation of the receptor ligand at the stage of preclinical studies of drug candidates. A drug with a long residence time can determine ligand-receptor selectivity (kinetic selectivity), maintain pharmacological activity of the drug at its low concentration in vivo. The paper discusses the theoretical basis of protein-ligand binding, molecular determinants that control the kinetics of the drug-receptor binding. Understanding the molecular features underlying the kinetics of receptor-ligand binding will contribute to the rational design of drugs with desired properties.
Assuntos
Desenho de Fármacos , Ligantes , Preparações Farmacêuticas/química , Ligação Proteica , Cinética , TermodinâmicaRESUMO
Identifying amino acid positions that determine the specific interaction of proteins with small molecule ligands, is required for search of pharmaceutical targets, drug design, and solution of other biotechnology problems. We studied applicability of an original method SPrOS (specificity projection on sequence) developed to recognize functionally significant positions in amino acid sequences. The method allows residues specific to functional subgroups to be determined within the protein family based on their local surroundings in amino acid sequences. The efficiency of the method has been estimated on the protein kinase family. The residues associated with the protein specificity to inhibitors have been predicted. The results have been verified using 3D structures of protein-ligand complexes. Three small molecule inhibitors have been tested. Residues predicted with SPrOS either in contacted the inhibitor or influenced the conformation of the ligand-binding area. Excluding close homologues from the studied set makes it possible to decrease the number of difficult to interpret positions. The expediency of this procedure was determined by the relationship between an inhibitory spectrum and phylogenic partition. Thus, the method efficiency has been confirmed by matching the prediction results with the protein 3D structures.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Análise de Sequência de Proteína/métodos , Animais , Sítios de Ligação , HumanosRESUMO
Beta-lactamases (EC 3.5.2.6) represent a superfamily containing more than 2,000 members: it includes genetically and functionally different bacterial enzymes capable to destroy the beta-lactam antibiotics. The most common are beta-lactamases of molecular class A with serine in the active center. Among them, TEM-type beta-lactamases are of particular interest from the viewpoint of studying the mechanisms of the evolution of resistance due to their broad polymorphism. To date, more than 200 sequences of TEM-type beta-lactamases have been described and more than 60 structures of different mutant forms have been presented in Protein Data Bank. We have considered the main structural features of the enzymes of this type with particular attention to the analysis of key drug resistance and the secondary mutations, their location relative to the active center and the surface of the protein globule. We have developed the BlaSIDB database (www.blasidb.org) which is an open information resource combining available data on 3D structures, amino acid sequences and nomenclature of the corresponding forms of beta-lactamases.
Assuntos
Bactérias/enzimologia , beta-Lactamases/química , beta-Lactamases/genética , Antibacterianos , Bases de Dados de Proteínas , Mutação , Estrutura Terciária de Proteína , Serina , Resistência beta-Lactâmica/genéticaRESUMO
Cytochromes P450 (CYP) are involved in numerous biochemical processes including metabolism of xenobiotics, biosynthesis of cholesterol, steroid hormones etc. Since some CYP catalyze indol oxidation to isatin, we have hypothesized that isatin can regulate protein-protein interactions (PPI) between components of the CYP system thus representing a (negative?) feedback mechanism. The aim of this study was to investigate a possible effect of isatin on interaction of human CYP with cytochrome b5 (CYB5A). Using the optical biosensor test system employing surface plasmon resonance (SPR) we have investigated interaction of immobilized CYB5A with various CYP in the absence and in the presence of isatin. The SPR-based experiments have shown that a high concentration of isatin (270 mM) increases Kd values for complexes CYB5A/CYP3Ð5 and CYB5A/CYP3A4 (twofold and threefold, respectively), but has no influence on complex formation between CYB5A and other CYP (including indol-metabolizing CYP2C19 and CYP2E1). Isatin injection to the optical biosensor chip with the preformed molecular complex CYB5A/CYP3A4 caused a 30%-increase in its dissociation rate. Molecular docking manipulations have shown that isatin can influence interaction of CYP3Ð5 or CYP3A4 with CYB5A acting at the contact region of CYB5A/CYP.
Assuntos
Citocromo P-450 CYP2C19/química , Citocromo P-450 CYP2E1/química , Citocromo P-450 CYP3A/química , Citocromos b5/química , Isatina/química , Sítios de Ligação , Enzima de Clivagem da Cadeia Lateral do Colesterol/química , Citocromo P-450 CYP2C9/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Soluções , Esteroide 11-beta-Hidroxilase/química , Esteroide 17-alfa-Hidroxilase/química , Ressonância de Plasmônio de SuperfícieRESUMO
Synthesis of b-lactamases is one of the common mechanisms of bacterial resistance to b-lactam antibiotics including penicillins and cephalosporins. The widespread use of antibiotics results in appearance of numerous extended-spectrum b-lactamase variants or resistance to inhibitors. Mutations of 92 residues of TEM type were found. Several mutations are the key mutations that determine the extension of spectrum of substrates. However, roles of the most associated mutations, located far from active site, remain unknown. We have investigated the role of associated mutations in structure of b-lactamase TEM-72, which contain two key mutation (G238S, E240K) and two associated mutations (Q39K, M182T) by means of simulation of molecular dynamics. The key mutation lead to destabilization of the protein globule, characterized by increased mobility of amino acid residues at high temperature of modelling. Mutation M182T lead to stabilization protein, whereas mutation Q39K is destabilizing mutation. It seems that the last mutation serves for optimization of conformational mobility of b-lactamase and may influence on enzyme activity.
Assuntos
Proteínas de Bactérias/química , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Resistência beta-Lactâmica , beta-Lactamases/química , Substituição de Aminoácidos , Proteínas de Bactérias/genética , Domínios Proteicos , beta-Lactamases/genéticaRESUMO
Plant seed knottins, mainly from the Cucurbitacea family, and sunflower seed trypsin inhibitor (SFTI 1) are the most low-molecular canonical peptide inhibitors of serine proteases. High efficiency of inhibition of various serine proteases, structure rigidity together with the possibility of limited variations of amino acid sequences, high chemical stability, lack of toxic properties, opportunity of production by either chemical synthesis or use of heterologous expression systems make these inhibitors attractive templates for design of new compounds for regulation of therapeutically significant serine protease activities. Hence the design of such compounds represents a prospective research field. The review considers structural characteristics of these inhibitors, their properties, methods of preparation and design of new analogs. Examples of successful employment of natural serine protease inhibitors belonging to knottin family and SFTI 1 as templates for the design of highly specific inhibitors of certain proteases are given.
Assuntos
Miniproteínas Nó de Cistina/química , Peptídeos Cíclicos/farmacologia , Proteínas de Plantas/química , Inibidores de Serina Proteinase/farmacologia , Animais , Miniproteínas Nó de Cistina/metabolismo , Descoberta de Drogas , Humanos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Proteínas de Plantas/metabolismo , Ligação Proteica , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/químicaRESUMO
The cytotoxic activity of synthetic progestins (pregna-D'-pentaranes) II-V full agonists of the progesterone receptor (PR) for PR-positive and PR-negative cells of human breast carcinoma was studied. These compounds were more active in the PR-positive MCF-7 cells than in the PR-negative MDA-MB-453 cells. Cytotoxic effects of tested compounds against normal epithelial MDCK cells were not found. Molecular modeling of studied steroids with PR showed that all progestins with close energy values can bind to the ligand binding domain (LBD) of PR and the magnitude of the energy exceeds the value estimated for the progesterone molecule. Thus, the studied progestins are active against different molecular subtypes of breast cancer and represent a promising class of chemical compounds for oncology.
Assuntos
Progestinas/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Cães , Humanos , Células MCF-7 , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Progestinas/química , Progestinas/toxicidade , Ligação Proteica , Receptores de Progesterona/metabolismoRESUMO
In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline--and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Compostos Heterocíclicos de 4 ou mais Anéis , Simulação de Acoplamento Molecular , Esteroide 17-alfa-Hidroxilase , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/químicaRESUMO
Renalase is a recently discovered secretory protein, which plays a certain (still poorly understood) role in regulation of blood pressure. The review summarizes own and literature data accumulated since the first publication on relanase (2005). Initial reports on FAD-dependent amine oxidase activity of this protein were not confirmed in independent experiments performed in different laboratories. In addition, proposed amine oxidase activity of circulating extracellular renalase requires the presence of FAD, which has not been detected either in blood or urinary renalase. Moreover, renalase excreted into urine lacks its N-terminal peptide, which is ultimately needed for accommodation of the FAD cofactor. Results of the Aliverti's group on NAD(P)H binding by renalase and weak diaphorase activity of this protein stimulated further studies of renalase as NAD(P)H oxidase catalyzing reaction of catecholamine co-oxidation. However, physiological importance of such extracellular catecholamine-metabolizing activity (demonstrated in one laboratory and not detected in another laboratory) remains unclear due to existence of much more active enzymatic systems (e.g. neutrophil NAD(P)H oxidase, xanthine oxidase/xanthine) in circulation, which can perform such co-oxidation reactions. Recently a-NAD(P)H oxidase/anomerase activity of renalase, which also pomotes oxidative conversion of b-NADH isomers inhibiting activity of NAD-dependent dehydrogenases, has been described. However, its possible contribution to the antihypertensive effect of renalase remains unclear. Thus, the antihypertensive effect of renalase still remains a phenomenon with unclear biochemical mechanim(s) and functions of intracellular and extracellular (circulating) renalases obviously differ.
Assuntos
Flavina-Adenina Dinucleotídeo/química , Flavina-Adenina Dinucleotídeo/metabolismo , Monoaminoxidase/química , Monoaminoxidase/metabolismo , NADPH Oxidases/química , NADPH Oxidases/metabolismo , Animais , HumanosRESUMO
The article summarized results of studies on active site structures of monoamine oxidases (MAO) performed in the Institute of Biomedical Chemistry (Russia) by computer modelling approaches. MAO, catalyzing the reaction of oxidative deamination of major neurotransmitter monoamines, exists in two highly homologous forms, MAO A and MAO B, distinguished by substrate specificity and inhibitor selectivity. The development of approaches for active site modelling of these enzymes (with unknown three-dimensional structures) started from analysis of relationship between the geometrical sizes of rigid indole and isatin derivatives and their inhibitory activity. These studies resulted in molding of the active site structures of MAO A and MAO B. These molds reflect the sizes and shapes of active sites of these enzymes. These mold models have been used for virtual screening of molecular databases for new inhibitors. The models obtained at different stages of MAO investigations have been compared with recently appeared three-dimensional structures of MAO A and MAO B.
Assuntos
Modelos Moleculares , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Domínio Catalítico , Humanos , Indóis/química , Isatina/química , Isatina/farmacologia , Conformação Proteica , Relação Quantitativa Estrutura-AtividadeRESUMO
Site-directed mutagenesis of Rhodospirillum rubrum L-asparaginase (RrA) was performed in order to identify sites of the protein molecule important for its therapeutic and physico-chemical properties. Ten multipoint mutant genes were obtained, and five recombinant RrA variants were expressed in E. coli BL21(DE3) cells and isolated as functionally active highly purified proteins. Protein purification was performed using Q-Sepharose and DEAE-Toyopearl chromatography. Overall yield of the active enzymes was 70-80 %, their specific activity at pH 7.4 and 37 °C varied of 140-210 U/mg. L-Glutaminase activity did not exceed 0.01 % of L-asparaginase activity. All RrA mutants showed maximum enzyme activity at pH 9.3-9.5 and 53-58 °C. Km and Vmax values for L-asparagine were evaluated for all mutants. Mutations G86P, D88H, M90K (RrAH), G121L, D123A (RrÐI) caused the loss of enzyme activity and confirmed the importance of these sites in the implementation of catalytic functions. Removal of four residues from C-terminal area of the enzyme (RrAK) resulted in the enzyme instability. Mutations D60K, F61L(RrÐD), and R118H, G120R(RrÐJ) led to the improvement of kinetic parameters and enzyme stabilization. Substitutions E149R, V150P (RrÐB) improved antineoplastic and cytotoxic activity of the RrA. A64V, E67K substitutions, especially in combination with E149R, V150P (RrÐE), considerably destabilized recombinant enzyme.
Assuntos
Asparaginase/química , Asparaginase/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Mutagênese Sítio-Dirigida/métodos , Rhodospirillum rubrum/enzimologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Asparaginase/biossíntese , Asparaginase/farmacologia , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Clonagem Molecular , Estabilidade Enzimática , Escherichia coli/genética , Humanos , Modelos Moleculares , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Rhodospirillum rubrum/genéticaRESUMO
New potential inhibitors of 5-lipoxygenase (5-LOX) based on the structure of 2-(3-benzoylphenyl)propanoic acid (an active component of the nonsteroidal antiinflammatory drug Ketoprofen) were designed using the SARD-21 program. The docking of these compounds in the active site of 5-LOX suggested that seven compounds can interact with this enzyme. Two of them can also be dual inhibitors of 5-LOX and two isoforms of cyclooxygenase.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Propionatos/farmacologia , Biocatálise/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Inibidores de Lipoxigenase/química , Modelos Moleculares , Estrutura Molecular , Propionatos/química , Relação Estrutura-AtividadeRESUMO
Protein-protein interactions (PPI) are involved in most of the essential processes that occur in organisms. In recent years, PPI have become the object of increasing attention in drug discovery, particularly for anti-HIV drugs. Although the use of combinations of existing drugs, termed highly active antiretroviral therapy (HAART), has revolutionized the treatment of HIV/AIDS, problems with these agents, such as the rapid emergence of drug-resistant HIV-1 mutants and serious adverse effects, have highlighted the need for further discovery of new drugs and new targets. Numerous investigations have shown that PPI play a key role in the virus's life cycle and that blocking or modulating them has a significant therapeutic potential. Here we summarize the recent progress in computer-aided design of PPI inhibitors, mainly focusing on the selection of the drug targets (HIV enzymes and virus entry machinery) and the utilization of peptides and small molecules to prevent a variety of protein-protein interactions (viral-viral or viral-host) that play a vital role in the progression of HIV infection.
Assuntos
Fármacos Anti-HIV/química , Desenho Assistido por Computador , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Humanos , Mapeamento de Interação de ProteínasRESUMO
Renalase is a recently discovered secretory enzyme responsible for selective degradation of blood catecholamines. The review summarizes literature data on expression of this enzyme and on its structure and functions. Special attention is paid to unsolved and questionable problems including: 1) prediction of the presence of FAD in the protein structure based on amino acid sequence similarity of renalase with known FAD-dependent enzymes; 2) identity of plasma and urinary renalase; 3) mechanism underlying conversion of inactive renalase into the active form.
Assuntos
Monoaminoxidase/química , Animais , Domínio Catalítico , Catecolaminas/metabolismo , Flavina-Adenina Dinucleotídeo/metabolismo , Humanos , Monoaminoxidase/sangue , Monoaminoxidase/urina , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Several activators of soluble guanylate cyclase were investigated as potential inhibitors of rat liver mitochondrial monoamine oxidases (MAO) A and B. They all fitted into the previously designed "molds" of substrate-inhibitor binding sites of these enzymes. However, only two of them, NO donors (7-nitro-benzotetrazine-1,3-dioxide (7-NBTDO) and benzodifuroxan), caused nonselective inhibition of MAO A and MAO B with IC(50) values of 1.3-1.6 and 6.8-6.3 microM, respectively. The inhibitory effect on both MAO A and MAO B was reduced by mitochondria wash suggesting reversible mode of the enzyme inhibition. There was no correlation between potency of MAO inhibition and activation of human platelet soluble guanylate cyclase. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) had no effect on the manifestation of MAO inhibition by benzodifuroxan and 7-NBTDO; however, at 50 microM concentration carboxy-PTIO caused potent inhibition of MAO A with minor effect on MAO B activity. The data suggest that nonselective inhibition of MAO A and MAO B by benzodifuroxan and 7-NBTDO can be attributed to the properties of the chemical structures of these compounds. The results of the present study demonstrate a real possibility for the development of a new generation of effective reversible nonselective MAO inhibitors exhibiting equal inhibitory activity with respect to both MAO A and MAO B.
Assuntos
Guanilato Ciclase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Animais , Benzoxazóis/química , Benzoxazóis/farmacologia , Sítios de Ligação , Guanilato Ciclase/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Nitrocompostos/química , Nitrocompostos/farmacologia , Óxidos/química , Óxidos/farmacologia , Conformação Proteica , Ratos , SolubilidadeRESUMO
Modern strategies of computer-aided drug design (CADD) are reviewed. The task of CADD in the pipeline of drug discovery is accelerating of finding the new lead compounds and their structure optimization for the following pharmacological tests. The main directions in CADD are based on the availability of the experimentally determined three-dimensional structure of the target macromolecule. If spatial structure is known the methods of structure-based drug design are used. In the opposite case the indirect methods of CADD based on the structures of known ligands (ligand-based drug design) are used. The interrelationship between the main directions of CADD is reviewed. The main CADD approaches of molecule de novo design and database mining are described. They include methods of molecular docking, de novo design, design of pharmacophore and quantity structure-activity relationship models. New ways and perspectives of CADD are discussed.
Assuntos
Desenho Assistido por Computador , Desenho de Fármacos , Biologia Computacional , Simulação por Computador , Computadores , Ligantes , Modelos Moleculares , Conformação Molecular , Software , Relação Estrutura-AtividadeRESUMO
Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures, properties of contact surfaces, and forces involved in protein-protein interactions. The properties of protein contact surfaces depend on their functions. The characteristics of contact surfaces of short-lived protein complexes share some similarities with the active sites of enzymes. The contact surfaces of permanent complexes resemble domain contacts or the protein core. It is reasonable to consider protein-protein complex formation as a continuation of protein folding. The contact surfaces of the protein complexes have unique structure and properties, so they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations have been undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or on the other hand, induce protein dimerization.