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1.
Front Pharmacol ; 12: 699535, 2021.
Article in English | MEDLINE | ID: mdl-35126098

ABSTRACT

The autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway plays a role in a variety of autoimmune diseases, such as rheumatoid arthritis or neurodegeneration. A link to the pathogenesis of glaucoma is suggested by an overactive ATX-LPA axis in aqueous humor samples of glaucoma patients. Analysis of such samples suggests that the ATX-LPA axis contributes to the fibrogenic activity and resistance to aqueous humor outflow through the trabecular meshwork. In order to inhibit or modulate this pathway, we developed a new series of ATX-inhibitors containing novel bicyclic and spirocyclic structural motifs. A potent lead compound (IC50 against ATX: 6 nM) with good in vivo PK, favorable in vitro property, and safety profile was generated. This compound leads to lowered LPA levels in vivo after oral administration. Hence, it was suitable for chronic oral treatment in two rodent models of glaucoma, the experimental autoimmune glaucoma (EAG) and the ischemia/reperfusion models. In the EAG model, rats were immunized with an optic nerve antigen homogenate, while controls received sodium chloride. Retinal ischemia/reperfusion (I/R) was induced by elevating the intraocular pressure (IOP) in one eye to 140 mmHg for 60 min, followed by reperfusion, while the other untreated eye served as control. Retinae and optic nerves were evaluated 28 days after EAG or 7 and 14 days after I/R induction. Oral treatment with the optimized ATX-inhibitor lead to reduced retinal ganglion cell (RGC) loss in both glaucoma models. In the optic nerve, the protective effect of ATX inhibition was less effective compared to the retina and only a trend to a weakened neurofilament distortion was detectable. Taken together, these results provide evidence that the dysregulation of the ATX-LPA axis in the aqueous humor of glaucoma patients, in addition to the postulated outflow impairment, might also contribute to RGC loss. The observation that ATX-inhibitor treatment in both glaucoma models did not result in significant IOP increases or decreases after oral treatment indicates that protection from RGC loss due to inhibition of the ATX-LPA axis is independent of an IOP lowering effect.

2.
ACS Chem Biol ; 14(1): 37-49, 2019 01 18.
Article in English | MEDLINE | ID: mdl-30452219

ABSTRACT

The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.


Subject(s)
DNA/genetics , Discoidin Domain Receptor 1/antagonists & inhibitors , Kidney/physiopathology , Nephritis, Hereditary/genetics , Animals , Autoantigens/genetics , Autoantigens/metabolism , Collagen Type IV/genetics , Collagen Type IV/metabolism , Discoidin Domain Receptor 1/metabolism , Disease Models, Animal , Epithelial Cells/metabolism , Kidney Function Tests , Mice , Mice, Knockout , Nephritis, Hereditary/physiopathology , Phosphorylation , Src Homology 2 Domain-Containing, Transforming Protein 1/metabolism
3.
Elife ; 62017 02 14.
Article in English | MEDLINE | ID: mdl-28195038

ABSTRACT

Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed ß-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.


Subject(s)
Antibodies, Protozoan/chemistry , Antibodies, Protozoan/metabolism , Antigens, Protozoan/chemistry , Antigens, Protozoan/metabolism , Malaria Vaccines/chemistry , Malaria Vaccines/metabolism , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Crystallography, X-Ray , Models, Molecular , Protein Binding , Protein Conformation
4.
J Med Chem ; 56(23): 9789-801, 2013 Dec 12.
Article in English | MEDLINE | ID: mdl-24224654

ABSTRACT

Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.


Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Animals , Cyclopentanes/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Humans , Mice , Proline/analogs & derivatives , Structure-Activity Relationship
5.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 6): 1124-37, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23695257

ABSTRACT

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic ß-cells, which leads to inactivation of the ß-cell proliferating activity of Tmem27. This role of BACE2 in the control of ß-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme ß-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.


Subject(s)
Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Immunoglobulin Fab Fragments/chemistry , Insulin-Secreting Cells/enzymology , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Animals , Area Under Curve , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Catalytic Domain , Crystallization , Humans , Immunoglobulin Fab Fragments/metabolism , Insulin-Secreting Cells/metabolism , Mice , Models, Molecular , Mutagenesis , Protein Conformation , Surface Plasmon Resonance , X-Ray Diffraction
6.
Biochem Biophys Res Commun ; 431(1): 70-5, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23277102

ABSTRACT

The human ether-a-go-go related gene (hERG) potassium channel plays a major role in the repolarization of the cardiac action potential. Inhibition of the hERG function by mutations or a wide variety of pharmaceutical compounds cause long QT syndrome and lead to potentially lethal arrhythmias. For detailed insights into the structural and biochemical background of hERG function and drug binding, the purification of recombinant protein is essential. Because the hERG channel is a challenging protein to purify, fast and easy techniques to evaluate different expression, solubilization and purification conditions are of primary importance. Here, we describe the generation of a set of 12 monoclonal antibodies against hERG. Beside their suitability in western blot, immunoprecipitation and immunostaining, these antibodies were used to establish a sandwich ELISA for the detection and relative quantification of hERG in different expression systems. Furthermore, a Fab fragment was used in fluorescence size exclusion chromatography to determine the oligomeric state of hERG after solubilization. These new tools can be used for a fast and efficient screening of expression, solubilization and purification conditions.


Subject(s)
Antibodies, Monoclonal/biosynthesis , Enzyme-Linked Immunosorbent Assay , Ether-A-Go-Go Potassium Channels/analysis , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Chromatography, Gel/methods , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/immunology , Ether-A-Go-Go Potassium Channels/isolation & purification , HEK293 Cells , Humans , Immunoglobulin Fab Fragments , Mice
7.
ChemMedChem ; 6(11): 2048-54, 2011 Nov 04.
Article in English | MEDLINE | ID: mdl-21898833

ABSTRACT

In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.


Subject(s)
Cathepsin L/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Halogens/chemistry , MAP Kinase Kinase 1/metabolism , Catalytic Domain , Cathepsin L/antagonists & inhibitors , Cathepsin L/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Ligands , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/chemistry , Protein Binding , Structure-Activity Relationship
8.
Acta Crystallogr D Biol Crystallogr ; 67(Pt 2): 119-23, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21245533

ABSTRACT

E-ISA247 (voclosporin) is a cyclosporin A analogue that is in late-stage clinical development for the treatment of autoimmune diseases and the prevention of organ graft rejection. The X-ray crystal structures of E-ISA247 and its stereoisomer Z-ISA247 bound to cyclophilin A have been determined and their binding affinities were measured to be 15 and 61 nM, respectively, by fluorescence spectroscopy. The higher affinity of E-ISA247 can be explained by superior van der Waals contacts between its unique side chain and cyclophilin A. Comparison with the known ternary structure including calcineurin suggests that the higher immunosuppressive efficacy of E-ISA247 relative to cyclosporin A could be a consequence of structural changes in calcineurin induced by the modified E-ISA247 side chain.


Subject(s)
Cyclophilin A/chemistry , Cyclosporine/chemistry , Immunosuppressive Agents/chemistry , Crystallography, X-Ray , Cyclophilin A/metabolism , Cyclosporine/metabolism , Humans , Immunosuppressive Agents/metabolism , Isomerism , Models, Molecular , Protein Binding , Protein Structure, Tertiary
10.
J Mol Biol ; 397(2): 508-19, 2010 Mar 26.
Article in English | MEDLINE | ID: mdl-20132826

ABSTRACT

The human fatty acid synthase (FAS) is a key enzyme in the metabolism of fatty acids and a target for antineoplastic and antiobesity drug development. Due to its size and flexibility, structural studies of mammalian FAS have been limited to individual domains or intermediate-resolution studies of the complete porcine FAS. We describe the high-resolution crystal structure of a large part of human FAS that encompasses the tandem domain of beta-ketoacyl synthase (KS) connected by a linker domain to the malonyltransferase (MAT) domain. Hinge regions that allow for substantial flexibility of the subdomains are defined. The KS domain forms the canonical dimer, and its substrate-binding site geometry differs markedly from that of bacterial homologues but is similar to that of the porcine orthologue. The didomain structure reveals a possible way to generate a small and compact KS domain by omitting a large part of the linker and MAT domains, which could greatly aid in rapid screening of KS inhibitors. In the crystal, the MAT domain exhibits two closed conformations that differ significantly by rigid-body plasticity. This flexibility may be important for catalysis and extends the conformational space previously known for type I FAS and 6-deoxyerythronolide B synthase.


Subject(s)
Fatty Acid Synthase, Type I/chemistry , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Protein Structure, Tertiary
11.
Structure ; 14(4): 713-23, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16615913

ABSTRACT

Carnitine palmitoyltransferases 1 and 2 (CPTs) facilitate the import of long-chain fatty acids into mitochondria. Modulation of the catalytic activity of the CPT system is currently under investigation for the development of novel drugs against diabetes mellitus. We report here the 1.6 A resolution structure of the full-length mitochondrial membrane protein CPT-2. The structure of CPT-2 in complex with the generic CPT inhibitor ST1326 ([R]-N-[tetradecylcarbamoyl]-aminocarnitine), a substrate analog mimicking palmitoylcarnitine and currently in clinical trials for diabetes mellitus treatment, was solved at 2.5 A resolution. These structures of CPT-2 provide insight into the function of residues involved in substrate binding and determination of substrate specificity, thereby facilitating the rational design of antidiabetic drugs. We identify a sequence insertion found in CPT-2 that mediates membrane localization. Mapping of mutations described for CPT-2 deficiency, a hereditary disorder of lipid metabolism, implies effects on substrate recognition and structural integrity of CPT-2.


Subject(s)
Carnitine O-Palmitoyltransferase/chemistry , Crystallography, X-Ray/methods , Diabetes Mellitus/metabolism , Amino Acid Sequence , Animals , Betaine/analogs & derivatives , Betaine/chemistry , Binding Sites , Carnitine/analogs & derivatives , Carnitine/chemistry , Diabetes Mellitus/therapy , Humans , Lipid Metabolism , Models, Chemical , Models, Molecular , Molecular Sequence Data , Mutation , Phenotype , Protein Binding , Protein Conformation , Protein Structure, Quaternary , Protein Structure, Secondary , Protein Structure, Tertiary , Proteins/chemistry , Rats , Substrate Specificity , Ultracentrifugation
12.
Mol Endocrinol ; 20(4): 809-30, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16373399

ABSTRACT

Partial agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), also termed selective PPARgamma modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPARgamma ligands. In a cocrystal with PPARgamma it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPARgamma-coactivator-1alpha (PGC1alpha) to the receptor, a feature shared with other selective PPARgamma modulators. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wild-type PGC1alpha but not its LXXLL-deficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative cross-talk of TNFalpha on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1alpha is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1alpha to favorable PPARgamma-target genes provides a possible molecular mechanism whereby partial PPARgamma agonists dissociate TG accumulation from insulin signaling.


Subject(s)
Heat-Shock Proteins/metabolism , Insulin/metabolism , Isoquinolines/pharmacology , PPAR gamma/agonists , Trans-Activators/metabolism , Transcription Factors/metabolism , Triglycerides/metabolism , Adipocytes/cytology , Adipocytes/drug effects , Adipocytes/metabolism , Amino Acid Sequence , Animals , Base Sequence , Binding Sites , Cell Line , Crystallography, X-Ray , DNA, Complementary/genetics , Glucose/metabolism , Heat-Shock Proteins/genetics , Humans , In Vitro Techniques , Isoquinolines/chemistry , Mice , Models, Molecular , Molecular Sequence Data , PPAR gamma/chemistry , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Protein Conformation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Trans-Activators/genetics , Transcription Factors/genetics , Tumor Necrosis Factor-alpha/pharmacology
13.
Bioconjug Chem ; 16(3): 504-17, 2005.
Article in English | MEDLINE | ID: mdl-15898716

ABSTRACT

The human recombinant Interferon-alpha(2a) (IFNalpha(2a)) is a potent drug (Roferon-A) to treat various types of cancer and viral diseases including Hepatitis B/C infections. To improve the pharmacological properties of the drug, a new pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side chain of IFNalpha(2a). (40)PEG-IFNalpha(2a) is a mixture of mainly six monopegylated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively. Here we report the detailed structural and biophysical characterization of (40)PEG-IFNalpha(2a) and its positional isomers, in comparison with IFNalpha(2a), using NMR spectroscopy, analytical ultracentrifugation, circular dichroism, fluorescence spectroscopy, and differential scanning calorimetry. Our results show that the three-dimensional structure of IFNalpha(2a) is not modified by the presence of the polymer in all positional isomers constituting (40)PEG-IFNalpha(2a). Regardless of where the PEG-polymer is attached, it adopts a very mobile and flexible random coil conformation, producing a shield for the protein without a permanent coverage of the protein surface. Hydrodynamic data indicate that the protein-attached PEG has a slightly more compact random-coil structure than the free PEG-polymer. Our results also provide evidence of significant structural and physicochemical advantages conferred by the pegylation: increase of the effective hydrodynamic volume and modification of the molecular shape, higher temperature stability, and reduced tendency for aggregation. These results are of tremendous pharmacological interest and benefit as was clinically shown with PEGASYS. This study constitutes a new standard for the characterization of pegylated proteins and enables an important step toward the understanding on a molecular level of the binding of (40)PEG-IFNalpha(2a) and its positional isomers to its cellular receptors.


Subject(s)
Interferon-alpha/chemistry , Polyethylene Glycols/chemistry , Humans , Interferon alpha-2 , Isomerism , Lysine/chemistry , Models, Molecular , Molecular Structure , Molecular Weight , Nuclear Magnetic Resonance, Biomolecular , Polymers/chemistry , Protein Denaturation , Protein Isoforms/chemistry , Protein Structure, Tertiary , Recombinant Proteins , Temperature
14.
Bioconjug Chem ; 16(3): 518-27, 2005.
Article in English | MEDLINE | ID: mdl-15898717

ABSTRACT

Type-I Interferons exert antiviral and antiproliferative activities through the binding to a common cell surface receptor comprising two subunits, IFNAR1 and IFNAR2. Human recombinant Interferon-alpha(2a) (IFNalpha(2a)) is a potent drug (Roferon-A) used to treat various cancers and viral diseases including Hepatitis B/C infections. To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a). Our binding studies, using the surface plasmon resonance technique, show that the pegylation does not abolish the binding to the receptor, but significantly reduces the affinity mainly due to a change of the association rate. The results are supported by modeling and simulation of the binding, using Self-Avoiding-Walk calculations for the polymer conformations. A correlation between the structural parameters and the kinetic and thermodynamic parameters of the binding of the positional isomers could be established. For the Isomer-K31 and -K164, the PEG-polymer attachment point is located in proximity to the binding interface, and the isomers display affinity in the range 150-520 nM in an enthalpy-driven binding process. In contrast for the Isomer-K134, -K131, -K121, and -K70, the PEG-polymer is attached remotely from the binding interface, and the isomers exhibit a higher affinity (32-76 nM) in an entropy-driven binding process. This study constitutes an essential collection of knowledge on which the interaction of (40)PEG-IFNalpha(2a) and its positional isomers with its cellular receptors can be better understood.


Subject(s)
Interferon-alpha/chemistry , Interferon-alpha/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Polyethylene Glycols/chemistry , Polyethylene Glycols/metabolism , Receptors, Interferon/chemistry , Receptors, Interferon/metabolism , Computer Simulation , Humans , Interferon alpha-2 , Isomerism , Kinetics , Models, Molecular , Molecular Weight , Nuclear Magnetic Resonance, Biomolecular , Polymers/chemistry , Polymers/metabolism , Protein Binding , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Protein Structure, Tertiary , Receptor, Interferon alpha-beta , Recombinant Proteins , Surface Plasmon Resonance , Temperature , Thermodynamics , Trypsin/metabolism
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