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Bone Aug 2002Matrix Gla protein (MGP) is an inhibitor of mineralization found in bone, cartilage, developing tissues, smooth muscle, and atherosclerotic plaques. MGP interaction with...
Matrix Gla protein (MGP) is an inhibitor of mineralization found in bone, cartilage, developing tissues, smooth muscle, and atherosclerotic plaques. MGP interaction with hydroxyapatite (HA) has been inferred by its function, but has never been measured directly. In this study, the influence of MGP antibody (x-MGP) binding, plasmin digestion, and various ions, including calcium and phosphate, on (125)I-labeled MGP-HA binding was examined. Nonlinear regression analysis of MGP binding yielded K(a) (association constant; approximately 8.0 x 10(4) M(-1)) and B(max) (maximum specific bound fraction of MGP; approximately 0.53). Anti-MGP antiserum reduced K(a) to less than half of control (0.33% x-MGP). Plasmin-digested MGP decreased HA binding parameters by almost a third, showing that protein binding and limited proteolysis greatly affected HA binding. The presence of free calcium ions significantly increased binding in a dose-dependent manner, with approximately 1 mmol/L calcium increasing K(a) by a factor of 2. Phosphate ions decreased binding significantly in a dose-dependent fashion, with approximately 1 mmol/L PO(4) decreasing K(a) by a third. Magnesium at approximately 1 mmol/L decreased K(a) significantly by half, but the effect was not dose-dependent. Carbonate, sulfate, and sodium ions had no significant effect on binding. MGP binding to HA is sensitive to protein binding, limited proteolysis, and the surrounding ionic environment.
Topics: Anions; Calcium; Calcium-Binding Proteins; Cations, Divalent; Dose-Response Relationship, Drug; Durapatite; Extracellular Matrix Proteins; Magnesium Chloride; Osmolar Concentration; Phosphates; Potassium Compounds; Protein Binding; Matrix Gla Protein
PubMed: 12151082
DOI: 10.1016/s8756-3282(02)00821-9 -
Nature Reviews. Drug Discovery May 2009
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Protein Binding; Psoriasis; Randomized Controlled Trials as Topic; Ustekinumab
PubMed: 19404310
DOI: 10.1038/nrd2878 -
Current Opinion in Structural Biology Aug 2019Optogenetic dimerizers are modular domains that can be utilized in a variety of versatile ways to modulate cellular biochemistry. Because of their modularity, many... (Review)
Review
Optogenetic dimerizers are modular domains that can be utilized in a variety of versatile ways to modulate cellular biochemistry. Because of their modularity, many applications using these tools can be easily transferred to new targets without extensive engineering. While a number of photodimerizer systems are currently available, the field remains nascent, with new optimizations for existing systems and new approaches to regulating biological function continuing to be introduced at a steady pace.
Topics: Light; Protein Binding; Protein Multimerization; Protein Structure, Quaternary; Proteins
PubMed: 30818200
DOI: 10.1016/j.sbi.2019.01.021 -
Protein and Peptide Letters Oct 2002Protein folding, binding, catalytic activity and molecular recognition all involve molecular movements, with varying extents. The molecular movements are brought upon... (Review)
Review
Protein folding, binding, catalytic activity and molecular recognition all involve molecular movements, with varying extents. The molecular movements are brought upon via flexible regions. Stemming from sequence, a fine tuning of electrostatic and hydrophobic properties of the protein fold determine flexible and rigid regions. Studies show flexible regions usually lack electrostatic interactions, such as salt-bridges and hydrogen-bonds, while the rigid regions often have larger number of such electrostatic interactions. Protein flexible regions are not simply an outcome of looser packing or instability, rather they are evolutionally selected. In this review article we highlight the significance of protein flexibilities in folding, binding and function, and their structural and thermodynamic determinants. Our electrostatic calculations and molecular dynamic simulations on an antibody-antigen complex further illustrate the importance of protein flexibilities in binding and function.
Topics: Antibody Affinity; Hydrophobic and Hydrophilic Interactions; Protein Binding; Protein Conformation; Protein Folding; Static Electricity; Structure-Activity Relationship; Thermodynamics
PubMed: 12370024
DOI: 10.2174/0929866023408508 -
Current Topics in Medicinal Chemistry 2011Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them... (Review)
Review
Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as "undruggable". Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies.
Topics: Animals; Drug Discovery; Humans; Protein Binding; Proteins
PubMed: 21320056
DOI: 10.2174/156802611794072632 -
Current Opinion in Structural Biology Feb 2002The structure of a protein-protein interaction, its affinity and thermodynamic characteristics depict a 'frozen' state of a complex. This picture ignores the kinetic... (Review)
Review
The structure of a protein-protein interaction, its affinity and thermodynamic characteristics depict a 'frozen' state of a complex. This picture ignores the kinetic nature of complex formation and dissociation, which are of major biological and biophysical interest. This review highlights recent advances in deciphering the kinetic pathway of protein-protein complexation, the nature of the encounter complex, transition state and intermediate along the reaction, and the effects of mutation, viscosity, pH and salt on association.
Topics: Animals; Binding Sites; Humans; Kinetics; Protein Binding; Thermodynamics
PubMed: 11839488
DOI: 10.1016/s0959-440x(02)00287-7 -
European Journal of Drug Metabolism and... 2003This study was designed to investigate the binding of clonidine to liver protein as well as the possible interactions with non-steroid anti-inflammatory drugs (NSAIDs)...
This study was designed to investigate the binding of clonidine to liver protein as well as the possible interactions with non-steroid anti-inflammatory drugs (NSAIDs) during the binding process in the rabbit. The binding of clonidine to slices (S) and homogenized slices (H) was estimated by a radioisotopic method following incubation with a mixture of cold and 3H-labelled clonidine in Ringer solution at 37 degrees C for 360 min. The binding of clonidine was assessed in the absence and presence of the following NSAIDs: flurbiprofen, ketoprofen, ibuprofen and acetylsalicylic acid. The results showed that the percentage of clonidine binding did not differ between intact and homogenized slices. The addition of all NSAIDs but ibuprofen, significantly decreased the protein binding of clonidine both in intact and homogenized liver slices. This finding could be attributed to the different affinity of ibuprofen for liver protein compared to the remaining NSAID's which may arise from a number of chemical properties including its dual Pka values.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonidine; Drug Interactions; Liver; Protein Binding; Rabbits
PubMed: 14527099
DOI: 10.1007/BF03190492 -
Current Opinion in Structural Biology Feb 2002Rigid body protein docking methods frequently yield false positive structures that have good surface complementarity, but are far from the native complex. The main... (Review)
Review
Rigid body protein docking methods frequently yield false positive structures that have good surface complementarity, but are far from the native complex. The main reason for this is the uncertainty of the protein structures to be docked, including the positions of solvent-exposed sidechains. Substantial efforts have been devoted to finding near-native structures by rescoring the docked conformations and employing various filters. An alternative approach emulates the process of protein-protein association, that is, first finding the region in which binding is likely to occur and then refining the complex while allowing for flexibility.
Topics: Binding Sites; Kinetics; Ligands; Protein Binding; Protein Conformation
PubMed: 11839487
DOI: 10.1016/s0959-440x(02)00286-5 -
Current Topics in Medicinal Chemistry 2013Protein:protein interactions are becoming increasingly significant as potential drug targets; however, the rational identification of small molecule inhibitors of such... (Review)
Review
Protein:protein interactions are becoming increasingly significant as potential drug targets; however, the rational identification of small molecule inhibitors of such interactions remains a challenge. Pharmacophore modelling is a popular tool for virtual screening of compound libraries, and has previously been successfully applied to the discovery of enzymatic inhibitors. However, the application of pharmacophore modelling in the field of protein:protein interaction inhibitors has historically been considered more of a challenge and remains limited. In this review, we explore the interaction mimicry by known inhibitors that originate from in vitro screening, demonstrating the validity of pharmacophore mapping in the generation of queries for virtual screening. We discuss the pharmacophore mapping methods that have been successfully employed in the discovery of first-in-class inhibitors. These successful cases demonstrate the usefulness of a "tool kit" of diverse strategies for application across a range of situations depending on the available structural information.
Topics: Drug Discovery; High-Throughput Screening Assays; Models, Molecular; Molecular Weight; Protein Binding; Proteins
PubMed: 23651479
DOI: 10.2174/1568026611313090003 -
Computational and Mathematical Methods... 2014By introducing the descriptors calculated from the molecular structure, the binding rates of plasma protein (BRPP) with seventy diverse drugs are modeled by a... (Comparative Study)
Comparative Study
By introducing the descriptors calculated from the molecular structure, the binding rates of plasma protein (BRPP) with seventy diverse drugs are modeled by a quantitative structure-activity relationship (QSAR) technique. Two algorithms, heuristic algorithm (HA) and support vector machine (SVM), are used to establish linear and nonlinear models to forecast BRPP. Empirical analysis shows that there are good performances for HA and SVM with cross-validation correlation coefficients Rcv(2) of 0.80 and 0.83. Comparing HA with SVM, it was found that SVM has more stability and more robustness to forecast BRPP.
Topics: Blood Proteins; Humans; Linear Models; Models, Theoretical; Pharmaceutical Preparations; Protein Binding; Quantitative Structure-Activity Relationship; Support Vector Machine
PubMed: 25161695
DOI: 10.1155/2014/957154