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structure-function relationships for the selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 by a novel androgen analog

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JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 2017年 174卷 257-264页

作者： Pham, Jenny H. Will, Catherine M. Mack, Vance L. Halbert, Matthew Conner, Edward Alexander Bucholtz, Kevin M. Thomas, James L. Dept Biomed Sci Macon GA 31207 USA Mercer Univ Dept Ob Gyn Sch Med Macon GA 31207 USA Mercer Univ Dept Chem Macon GA 31207 USA

3 beta-Hydroxysteroid dehydrogenase type 1 (3 beta-HSD1) is selectively expressed in human placenta, mammary glands and breast tumors in women. Human 3 beta-HSD2 is selectively expressed in adrenal glands and ovaries. Based on AutoDock 3 and 4 results, we have exploited key differences in the amino acid sequences of 3 beta-HSD1 (Ser 194, Arg195) and 3 beta-HSD2 (Gly194, Pro195) by designing a selective inhibitor of 3 beta-HSD1. 2,16-Dicyano-4,5-epoxy-androstane-3,17-dione (16-cyano-17-keto-trilostane or DiCN-AND) was synthesized in a 4-step procedure from androstenedione. In purified 3 beta-HSD inhibition studies, DiCN-AND competitively inhibited 3 beta-HSD1 with K-i = 4.7 mu M and noncompetitively inhibited 3 beta-HSD2 with a 6.5-fold higher K-i = 30.7 mu M. We previously reported similar isoenzyme-specific inhibition profiles for trilostane. Based on our docking results, we created, expressed and purified the chimeric S194G-1 mutant of 3 beta-HSD1. Trilostane inhibited S194G-1 (K-i = 0.67 mu M) with a noncompetitive mode compared to its 6.7-fold higher affinity, competitive inhibition of 3 beta-HSD1 (K-i = 0.10 mu M). DiCN-AND inhibited S194G-1 with a 6.3-fold higher K-i (29.5 mu M) than measured for 3 beta-HSD1 (K-i = 4.7 mu M) but with the same competitive mode for both enzyme species. Since DiCN-AND noncompetitively inhibits 3 beta-HSD2, which has the Gly194 and Pro195 of 3 beta-HSD2 in place of the Ser194 and Arg195 in 3 beta-HSD1, this suggests that Arg195 alone in 3 beta-HSD1 or S194G-1 is required to bind DiCN-AND in the substrate binding site (competitive inhibition). However, both Ser194 and Arg195 are required to bind trilostane in the 3 beta-HSD1 substrate site based on its noncompetitive inhibition of S194G-1 and 3 beta-HSD2. In support of this hypothesis, DiCN-AND inhibited our chimeric R195P-1 mutant noncompetitively with a K-i = 41.3 mu M (similar to the 3 beta-HSD2 inhibition profile). Since DiCN-AND competitively inhibited S194G-1 that still conta

关键词： 3 beta-Hydroxysteroid dehydrogenase Short-chain dehydrogenase/reductase Mutagenesis structure-function relationships

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Biochemical characterization of the selenoproteome in Gallus gallus via bioinformatics analysis: structure-function relationships and interactions of binding molecules

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METALLOMICS 2017年第2期9卷 124-131页

作者： Zhu, Shi-Yong Li, Xue-Nan Sun, Xiao-Chen Lin, Jia Li, Wei Zhang, Cong Li, Jin-Long Northeast Agr Univ Coll Vet Med Harbin 150030 Peoples R China

Knowledge about mammalian selenoproteins is increasing. However, the selenoproteome of birds remains considerably less understood, especially concerning its biochemical characterization, structure-function relationships and the interactions of binding molecules. In this work, the SECIS elements, subcellular localization, protein domains and interactions of binding molecules of the selenoproteome in Gallus gallus were analyzed using bioinformatics tools. We carried out comprehensive analyses of the structure-function relationships and interactions of the binding molecules of selenoproteins, to provide biochemical characterization of the selenoproteome in Gallus gallus. Our data provided a wealth of information on the biochemical functions of bird selenoproteins. Members of the selenoproteome were found to be involved in various biological processes in chickens, such as in antioxidants, maintenance of the redox balance, Se transport, and interactions with metals. Six membrane-bound selenoproteins (SelI, SelK, SelS, SelT, DIO1 and DIO3) played important roles in maintaining the membrane integrity. Chicken selenoproteins were classified according to their ligand binding sites as zinc-containing matrix metalloselenoproteins (Sep15, MsrB1, SelW and SelM), POP-containing selenoproteins (GPx1-4), FAD-interacting selenoproteins (TrxR1-3), secretory transport selenoproteins (GPx3 and SelPa) and other selenoproteins. The results of our study provided new evidence for the unknown biological functions of the selenoproteome in birds. Future research is required to confirm the novel biochemical functions of bird selenoproteins.

关键词： Avifauna Selenoproteins structure-function relationships Gallus gallus Biological Process

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Effect of formulation on structure-function relationships of concentrated emulsions: Rheological, tribological, and microstructural characterization

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FOOD HYDROCOLLOIDS 2017年 72卷 11-26页

作者： Anvari, Mohammad Joyner (Melito), Helen S. Univ Idaho Sch Food Sci 875 Perimeter DrMS 2312 Moscow ID 83844 USA

Since concentrated emulsions are the basis for many commercial products, conducting comprehensive studies on structureefunction relationships of emulsion systems is necessary for targeted product design. Hence, the objectives of this study were to 1) characterize the effects of fish gelatin concentration and oil phase volume fraction on the rheological, tribological and microstructural properties of concentrated emulsions and 2) determine structureefunction relationships based on the measured parameters. Emulsions were prepared using different amounts of oil and fish gelatin, and characterized by rheometry and microscopy. Emulsions containing higher oil or fish gelatin concentrations had greater stability to creaming, larger critical strains, and lower friction profiles. However, they exhibited increased nonlinear behavior under large amplitude oscillatory shear. These results were ascribed to increased homogeneity, higher network extension, and smaller oil droplets in emulsions with higher protein or oil concentrations. These results can be used to incorporate concentrated emulsions in emulsion-based formulations. (C) 2017 Elsevier Ltd. All rights reserved.

关键词： Concentrated emulsion Rheology structure-function relationships Tribology

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An observation that illustrates most T cell receptor structure-function relationships

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IMMUNOLOGIC RESEARCH 2017年第6期65卷 1095-1098页

作者： Cohn, Melvin Salk Inst Biol Studies Conceptual Immunol Grp 10010 N Torrey Pines Rd La Jolla CA 92037 USA

The Standard model of the T cell receptor (TCR) structure-function relationships is based on an analogy with the B cell receptor. Here a single observation is analyzed to show why this appears to be untenable. The Standard model cannot account for allele-specific recognition of theMHC-encoded presenter of peptide (R) by the TCR nor can it adequately explain alloreactivity. The competing framework is based on the assumptions that (1) single V-domains recognize the alleles of R, (2) restrictive reactivity is peptide specific, whereas alloreactivity is peptide unspecific, and (3) the TCR is born in two conformations, which display reciprocal behaviors (see text). In any case, whatever position one takes regarding these two models, competing conceptualizations are of crucial value in guiding experimentation, not to mention creative thinking.

关键词： TCR Restrictive recognition of peptide Alloreactivity Signaling structure-function relationships

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structure-function relationships of human JmjC oxygenases - demethylases versus hydroxylases

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CURRENT OPINION IN STRUCTURAL BIOLOGY 2016年 41卷 62-72页

作者： Markolovic, Suzana Leissing, Thomas M. Chowdhury, Rasheduzzaman Wilkins, Sarah E. Lu, Xin Schofield, Christopher J. Univ Oxford Chem Res Lab Mansfield Rd Oxford OX1 3TA England Univ Oxford Ludwig Inst Canc Res Nuffield Dept Clin Med Old Rd Campus Res BldgOld Rd Campus Oxford OX3 7DQ England

The Jumonji-C (JmjC) subfamily of 2-oxoglutarate (20G)-dependent oxygenases are of biomedical interest because of their roles in the regulation of gene expression and protein biosynthesis. Human JmjC 20G oxygenases catalyze oxidative modifications to give either chemically stable alcohol products, or in the case of N-epsilon-methyl lysine demethylation, relatively unstable hemiaminals that fragment to give formaldehyde and the demethylated product. Recent work has yielded conflicting reports as to whether some JmjC oxygenases catalyze N-methyl group demethylation or hydroxylation reactions. We review JmjC oxygenase-catalyzed reactions within the context of structural knowledge, highlighting key differences between hydroxylases and demethylases, which have the potential to inform on the possible type(s) of reactions catalyzed by partially characterized or un-characterized JmjC oxygenases in humans and other organisms.

关键词： Human Gene Expression Regulation structure-function relationships hydroxylases Oxygenases demethylation alcohol product

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Amylin structure-function relationships and receptor pharmacology: implications for amylin mimetic drug development

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BRITISH JOURNAL OF PHARMACOLOGY 2016年第12期173卷 1883-1898页

作者： Bower, Rebekah L. Hay, Debbie L. Univ Auckland Sch Biol Sci Auckland 1 New Zealand Univ Auckland Maurice Wilkins Ctr Mol Biodiscovery Auckland 1 New Zealand

Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA-approved drug used in insulin-requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin-mimetic compounds. Given that amylin-mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity-modifying proteins. This review explores what is known of the structure-function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids.

关键词： drug development Islet Amyloid Polypeptide Receptor useful area structure-function relationships pramlintide Drug Design peptide sequence

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structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein

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NUCLEIC ACIDS RESEARCH 2015年第18期43卷 8801-8816页

作者： Perugino, Giuseppe Miggiano, Riccardo Serpe, Mario Vettone, Antonella Valenti, Anna Lahiri, Samarpita Rossi, Franca Rossi, Mose Rizzi, Menico Ciaramella, Maria Natl Res Council Italy Inst Biosci & Bioresources I-80125 Naples Italy Univ Piemonte Orientale DiSF Dipartimento Sci Farmaco I-28100 Novara Italy

Alkylated DNA-protein alkyltransferases repair alkylated DNA bases, which are among the most common DNA lesions, and are evolutionary conserved, from prokaryotes to higher eukaryotes. The human ortholog, hAGT, is involved in resistance to alkylating chemotherapy drugs. We report here on the alkylated DNA-protein alkyltransferase, SsOGT, from an archaeal species living at high temperature, a condition that enhances the harmful effect of DNA alkylation. The exceptionally high stability of SsOGT gave us the unique opportunity to perform structural and biochemical analysis of a protein of this class in its post-reaction form. This analysis, along with those performed on SsOGT in its ligand-free and DNA-bound forms, provides insights in the structure-function relationships of the protein before, during and after DNA repair, suggesting a molecular basis for DNA recognition, catalytic activity and protein post-reaction fate, and giving hints on the mechanism of alkylation-induced inactivation of this class of proteins.

关键词： Alkyl and Aryl Transferases damage repair structure-function relationships Biochemical analysis DNA Alkylation Protein

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A Novel Missense Mutation in the HSD3B2 Gene, Underlying Nonsalt-Wasting Congenital Adrenal Hyperplasia. New Insight Into the structure-function relationships of 3β-Hydroxysteroid Dehidrogenase Type II

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JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2015年第1期100卷 E191-E196页

作者： Sonia Baquedano, Maria Ciaccio, Marta Marino, Roxana Perez Garrido, Natalia Ramirez, Pablo Maceiras, Mercedes Turjanski, Adrian Defelipe, Lucas A. Rivarola, Marco A. Belgorosky, Alicia Consejo Nacl Invest Cient & Tecn Hosp Pediat Garrahan Endocrine Serv RA-1033 Buenos Aires DF Argentina Univ Buenos Aires Fac Ciencias Exactas & Nat CONICET Biol Chem DeptInst Quim Fis Mat Medio Ambiente & Buenos Aires DF Argentina

Context: 3 beta HSD2 is a bifunctional microsomal NAD(+)-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting Delta 5-steroids to Delta 4-steroids. 3 beta HSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by recessive loss-of-function HSD3B2 mutations. Objective: The aim was to define the pathogenic consequences of a novel missense mutation in the HSD3B2 gene. Patient: We report a 7-month-old 46, XX girl referred because of precocious pubarche and postnatal clitoromegaly. Hormonal profile showed inadequate glucocorticoid levels, increased 17OHP and renin levels, and very high DHEAS levels, suggestive of compensated nonsalt-losing 3 beta HSD2 deficiency. Design and Results: Direct sequencing revealed a novel, homozygous, pG250V HSD3B2 mutation. In vitro analysis in intact COS-7 cells showed impaired enzymatic activity for the conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione (20% and 27% of WT at 6 h, respectively). G250V-3 beta HSD2 decreased the V-max for progesterone synthesis without affecting the Km for pregnenolone. Western blot and immunofluorescence suggested that p.G250V mutation has no effect on the expression and intracellular localization of the mutant protein. Molecular homology modeling predicted that mutant V250 affected an L239-Q251 loop next to a beta-sheet structure in the NAD+-binding domain. Conclusions: We identified a novel p.G250V mutation of HSD3B2 which causes an incomplete loss of enzymatic activity, explaining the compensated nonsalt loss phenotype. In vitro and in silico experiments provided insight into the structure-function relationship of the 3 beta HSD2 protein suggesting the importance of the L239-Q251 loop for the catalytic activity of the otherwise stable 3 beta HSD2 enzyme.

关键词： Adrenogenital Syndrome structure-function relationships Missense Mutation RNU1-4 gene HSD3B2 gene

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Ensemble-function relationships: From qualitative to quantitative relationships between protein structure and function

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JOURNAL OF STRUCTURAL BIOLOGY 2025年第1期217卷 108152页

作者： Yabukarski, Filip Bristol Myers Squibb Prot Homeostasis Struct Biol Grp San Diego CA 92121 USA

structure-function relationships are deeply rooted in modern biochemistry and structural biology and have provided the basis for our understanding of how protein structure defines function. While structure-function relationships continue to provide invaluable qualitative information, they cannot, in principle, provide the quantitative information ultimately needed to fully understand how proteins function and to make quantitative predictions about changes in activity from changes in sequence and structure. These limitations appear to arise from fundamental principles of physics, which dictate that proteins exist as interchanging ensembles of conformations, rather than as static structures that underly conventional structure-function relationships. This perspective discusses the concept of ensemble-function relationships as quantitative relationships that build on and extend traditional structure-function relationships. The concepts of free energy landscapes and conformational ensembles and their application to proteins are reviewed. The perspective summarizes a range of approaches that can provide conformational ensemble information and focuses on X-ray crystallography methods for obtaining experimental protein conformational ensembles. Focusing on enzymes as archetypes of protein function, recent literature examples are reviewed that used ensemble-function relationships to understand how protein residues contribute to function and how changes in protein sequence and structure impact activity, leading to new models and providing previously inaccessible mechanistic insights. Potential applications of conformational ensembles and ensemble-function relationships to protein design are examined. The perspective concludes with current limitations of the ensemble-function relationships and potential paths forward toward the next generation of quantitative ensemble-function models.

关键词： Protein structure structure-function relationships X-ray crystallography Conformational ensembles Ensemble-function relationships

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structure-function relationships in Hydrophobins: Probing the Role of Charged Side Chains

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APPLIED AND ENVIRONMENTAL MICROBIOLOGY 2013年第18期79卷 5533-5538页

作者： Lienemann, Michael Gandier, Julie-Anne Joensuu, Jussi J. Iwanaga, Atsushi Takatsuji, Yoshiyuki Haruyama, Tetsuya Master, Emma Tenkanen, Maija Linder, Markus B. VTT Tech Res Ctr Finland Espoo Finland Univ Toronto Dept Chem Engn & Appl Chem Toronto ON Canada Kyushu Inst Technol Dept Biol Funct & Engn Kitakyushu Fukuoka 804 Japan Univ Helsinki Dept Food & Environm Sci Helsinki Finland Aalto Univ Sch Chem Technol Dept Biotechnol & Chem Technol Espoo Finland

Hydrophobins are small fungal proteins that are amphiphilic and have a strong tendency to assemble at interfaces. By taking advantage of this property, hydrophobins have been used for a number of applications: as affinity tags in protein purification, for protein immobilization, such as in foam stabilizers, and as dispersion agents for insoluble drug molecules. Here, we used site-directed mutagenesis to gain an understanding of the molecular basis of their properties. We especially focused on the role of charged amino acids in the structure of hydrophobins. For this purpose, fusion proteins consisting of Trichoderma reesei hydrophobin I (HFBI) and the green fluorescent protein (GFP) that contained various combinations of substitutions of charged amino acids (D30, K32, D40, D43, R45, K50) in the HFBI structure were produced. The effects of the introduced mutations on binding, oligomerization, and partitioning were characterized in an aqueous two-phase system. It was found that some substitutions caused better surface binding and reduced oligomerization, while some showed the opposite effects. However, all mutations decreased partitioning in surfactant systems, indicating that the different functions are not directly correlated and that partitioning is dependent on finely tuned properties of hydrophobins. This work shows that not all functions in self-assembly are connected in a predictable way and that a simple surfactant model for hydrophobin function is insufficient.

关键词： relationships hydrophobins Probing assemblies structure-function relationships hydrophobin partitions Exploration with a probe Green Fluorescent Proteins

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