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solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer

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JOURNAL OF BIOLOGICAL CHEMISTRY 2019年第31期294卷 11920-11933页

作者： Khan, Nazimuddin Shah, Parag P. Ban, David Trigo-Mourino, Pablo Carneiro, Marta G. DeLeeuw, Lynn Dean, William L. Trent, John O. Beverly, Levi J. Konrad, Manfred Lee, Donghan Sabo, T. Michael Univ Louisville James Graham Brown Canc Ctr Dept Med 505 S Hancock St Louisville KY 40202 USA Max Planck Inst Biophys Chem Dept NMR Based Struct Biol Fassberg 11 D-37077 Gottingen Germany Max Planck Inst Biophys Chem Enzyme Biochem Grp Fassberg 11 D-37077 Gottingen Germany Merck Res Labs Biochem & Biophys 2015 Galloping Hill Rd Kenilworth NJ 07033 USA Merck Res Labs Struct Elucidat Grp Analyt Enabling Technol 2015 Galloping Hill Rd Kenilworth NJ 07033 USA ZoBio BV Biopartner Bldg 2JH Oortweg 19 NL-2333 CH Leiden Netherlands

Human guanylate kinase (hGMPK) is the only known enzyme responsible for cellular GDP production, making it essential for cellular viability and proliferation. Moreover, hGMPK has been assigned a critical role in metabolic activation of antiviral and antineoplastic nucleoside-analog prodrugs. Given that hGMPK is indispensable for producing the nucleotide building blocks of DNA, RNA, and cGMP and that cancer cells possess elevated GTP levels, it is surprising that a detailed structural and functional characterization of hGMPK is lacking. Here, we present the first high-resolution structure of hGMPK in the apo form, determined with NMR spectroscopy. The structure revealed that hGMPK consists of three distinct regions designated as the LID, GMP-binding (GMP-BD), and CORE domains and is in an open configuration that is nucleotide binding-competent. We also demonstrate that nonsynonymous single-nucleotide variants (nsSNVs) of the hGMPK CORE domain distant from the nucleotide-binding site of this domain modulate enzymatic activity without significantly affecting hGMPK's structure. Finally, we show that knocking down the hGMPK gene in lung adenocarcinoma cell lines decreases cellular viability, proliferation, and clonogenic potential while not altering the proliferation of immortalized, noncancerous human peripheral airway cells. Taken together, our results provide an important step toward establishing hGMPK as a potential biomolecular target, from both an orthosteric (ligand-binding sites) and allosteric (location of CORE domain-located nsSNVs) standpoint.

关键词： nuclear magnetic resonance (NMR) protein structure enzyme kinetics enzyme mutation lung cancer guanylate kinase hGMPK non-synonymous single nucleotide variants (nsSNV) solution structure

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solution structure of family 21 carbohydrate-binding module from Rhizopus oryzae glucoamylase

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BIOCHEMICAL JOURNAL 2007年第Pt 1期403卷 21-30页

作者： Liu, Yu-Nan Lai, Yen-Ting Chou, Wei-I Chang, Margaret Dah-Tsyr Lyu, Ping-Chiang Natl Tsing Hua Univ Inst Bioinformat & Struct Biol Hsinchu 30013 Taiwan Natl Tsing Hua Univ Inst Mol & Cell Biol Hsinchu 30013 Taiwan Natl Tsing Hua Univ Dept Life Sci Hsinchu 30013 Taiwan

CBMs (carbohydrate-binding modules) function independently to assist carbohydrate-active enzymes. Family 21 CBMs contain approx. 100 amino acid residues, and some members have starch-binding functions or glycogen-binding activities. We report here the first structure of a family 21 CBM from the SBD (starch-binding domain) of Rhizopus oryzae glucoamylase (RoCBM21) determined by NMR spectroscopy. This CBM has a beta-sandwich fold with an immunoglobulin-like structure. Ligand-binding properties of RoCBM21 were analysed by chemical-shift perturbations and automated docking. Structural comparisons with previously reported SBDs revealed two types of topologies, namely type I and type II, with CBM20, CBM25, CBM26 and CBM41 showing type I topology, with CBM21 and CBM34 showing type II topology. According to the chemical-shift perturbations, RoCBM21 contains two ligand-binding sites. Residues in site II are similar to those found in the family 20 CBM from Aspergillus niger glucoamylase (AnCBM20). Site I, however, is embedded in a region with unique sequence motifs only found in some members of CBM21s. Additionally, docking of beta-cyclodextrin and maltooligosaccharides highlights that side chains of Y83 and W47 (one-letter amino acid code) form the central part of the conserved binding platform in the SBD. The structure of RoCBM21 provides the first direct evidence of the structural features and the basis for protein-carbohydrate recognition from an SBD of CBM21.

关键词： carbohydrate-active enzyme carbohydrate-binding module (CBM) glucoamylase Rhizopus oryzae solution structure starch-binding domain (SBD)

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solution structure of the C-terminal X domain of the measles virus phosphoprotein and interaction with the intrinsically disordered C-terminal domain of the nucleoprotein

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JOURNAL OF MOLECULAR RECOGNITION 2010年第5期23卷 435-447页

作者： Gely, Stephane Lowry, David F. Bernard, Cedric Jensen, Malene R. Blackledge, Martin Costanzo, Stephanie Bourhis, Jean-Marie Darbon, Herve Daughdrill, Gary Longhi, Sonia CNRS Architecture & Fonct Macromol Biol AFMB UMR 6098 F-13288 Marseille 09 France Univ Aix Marseille 1 F-13288 Marseille 09 France Univ Aix Marseille 2 F-13288 Marseille 09 France Univ S Florida Ctr Biomol Identificat & Targeted Therapeut Tampa FL 33612 USA Univ S Florida Dept Cell Biol Microbiol & Mol Biol Tampa FL 33612 USA

In this report, the solution structure of the nucleocapsid-binding domain of the measles virus phosphoprotein (XD, aa 459-507) is described. A dynamic description of the interaction between XD and the disordered C-terminal domain of the nucleocapsid protein, (N-TAIL, aa 401-525), is also presented. XD is an all alpha protein consisting of a three-helix bundle with an up-down-up arrangement of the helices. The solution structure of XD is very similar to the crystal structures of both the free and bound form of XD. One exception is the presence of a highly dynamic loop encompassing XD residues 489-491, which is involved in the embedding of the alpha-helical XD-binding region of N-TAIL. Secondary chemical shift values for full-length N-TAIL were used to define the precise boundaries of a transient helical segment that coincides with the XD-binding domain, thus shedding light on the pre-recognition state of N-TAIL. Titration experiments with unlabeled XD showed that the transient alpha-helical conformation of N-TAIL is stabilized upon binding. Lineshape analysis of NMR resonances revealed that residues 483-506 of N-TAIL are in intermediate exchange with XD, while the 475-482 and 507-525 regions are in fast exchange. The N-TAIL resonance behavior in the titration experiments is consistent with a complex binding model with more than two states. Copyright (C) 2010 John Wiley & Sons, Ltd.

关键词： measles virus nucleoprotein phosphoprotein solution structure NMR spectral assignment intrinsic disorder induced folding disorder-to-order transitions residual structure conformer selection

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solution structure OF GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE FROM HALOARCULA-VALLISMORTIS

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BIOPHYSICAL CHEMISTRY 1995年第3期54卷 219-227页

作者： EBEL, C ALTEKAR, W LANGOWSKI, J URBANKE, C FOREST, E ZACCAI, G BHABHA ATOM RES CTR DEPT RADIAT BIOL & BIOCHEM BOMBAY 400085 MAHARASHTRA INDIA EUROPEAN MOLEC BIOL LAB GRENOBLE OUTSTN F-38042 GRENOBLE FRANCE HANNOVER MED SCH INST BIOPHYS CHEM W-3000 HANNOVER 61 GERMANY

The subunit molecular mass of glyceraldehyde-3-phosphate dehydrogenase from the extreme halophile Haloarcula vallismortis (hGAPDH) was determined by mass spectrometry to be 35990 +/- 80 daltons, similar to other GAPDHs. Complementary density, sedimentation and light scattering experiments showed the protein to be a tetramer that binds 0.18 +/- 0.10 gram of water and 0.07 +/- 0.02 gram of KCl per gram of protein, in multimolar KCl solutions. At low salt (below 1 M), the tetramer dissociated into unfolded monomers. This is the third halophilic protein for which solvent interactions were measured. The extent of these interactions depends on the protein, but all form an invariant particle, in multimolar NaCl or KCl solutions, that binds a high proportion of salt when compared to non-halophilic proteins.

关键词： HALOPHILIC PROTEIN GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE solution structure SOLVENT INTERACTION MOLAR MASS DETERMINATION

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solution structure and glycophorin C binding studies of the protein 4.1R FERM α-lobe domain

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PROTEINS-structure FUNCTION AND BIOINFORMATICS 2009年第1期76卷 255-260页

作者： Kusunoki, Hideki Kohno, Toshiyuki Mitsubishi Kagaku Inst Life Sci MITILS Tokyo 1948511 Japan

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solution structure of MUL1-RING domain and its interaction with p53 transactivation domain

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2019年第2期516卷 533-539页

作者： Lee, Min-Sung Lee, Sang-Ok Lee, Mi-Kyung Yi, Gwan-Su Lee, Chong-Kil Ryu, Kyoung-Seok Chi, Seung-Wook KRIBB Div Biomed Res Dis Target Struct Res Ctr Daejeon 34141 South Korea Univ Sci & Technol KRIBB Sch Biosci Dept Proteome Struct Biol 217 Gajeong Ro Daejeon 34113 South Korea Univ Sci & Technol Dept Bioanalyt Sci 217 Gajeong Ro Daejeon 34113 South Korea Korea Basic Sci Inst Prot Struct Res Grp 162 Yeongudanji Ro Cheongju 28119 Chungcheongbuk South Korea Korea Adv Inst Sci & Technol Dept Bio & Brain Engn Daejeon 34141 South Korea Chungbuk Natl Univ Coll Pharm Cheongju 28644 South Korea

Mitochondrial E3 ubiquitin ligase 1 (MUL1) is a multifunctional mitochondrial protein involved in various biological processes such as mitochondrial dynamics, cell growth, apoptosis, and mitophagy. MUL1 mediates the ubiquitylation of mitochondrial p53 for proteasomal degradation. Although the interaction of MUL1-RING domain with its substrate, p53, is a unique mechanism in RING-mediated ubiquitylation, the molecular basis of this process remains unknown. In this study, we determined the solution structure of the MUL1-RING domain and characterized its interaction with the p53 trans activation domain (p53-TAD) by nuclear magnetic resonance (NMR) spectroscopy. The overall structure of the MUL1-RING domain is similar to those of RING domains of other E3 ubiquitinases. The MUL1-RING domain adopts a beta beta alpha beta fold with three anti-parallel beta-strands and one alpha-helix, containing a canonical cross-brace motif for the ligation of two zinc ions. Through NMR chemical shift perturbation experiments, we determined the p53-TAD-binding site in the MUL1-RING domain and showed that the MUL1-RING domain interacts mainly with the p53-TAD2 subdomain composed of residues 39-57. Taken together, our results provide a molecular basis for the novel recognition mechanism of the p53-TAD substrate by the MUL1-RING domain. (C) 2019 Elsevier Inc. All rights reserved.

关键词： Mitochondrial E3 ubiquitin ligase 1 p53 Transactivation domain RING domain solution structure Protein-protein interaction

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solution structure of reduced microsomal rat cytochrome b(5)

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EUROPEAN JOURNAL OF BIOCHEMISTRY 1997年第1期249卷 270-279页

作者： Banci, L Bertini, I Ferroni, F Rosato, A UNIV FLORENCE DEPT CHEM I-50121 FLORENCE ITALY

The solution structure of the major form of the reduced soluble fragment of rat microsomal cytochrome b(5) has been solved through H-1-NMR spectroscopy. The protein contains 98 amino acids. Proton assignment was available for residues 1-94, except 90 [Guiles, R. D., Basus, V. J., Kuntz, I. D. & Waskell, L. (1992) Biochemistry 31, 11365-11375] and has been confirmed. From 1722 NOEs, of which 1203 were found to be meaningful, a family of 40 energy-minimized structures has been obtained with average backbone rmsd (for residues 5-89) of 0.078+/-0.018 nm and average target function of 0.0045 nm(2), no distance violations being larger than 0.029 nm. The structure has been compared with the X-ray structure of the oxidized rat mitochondrial isoenzyme and with that of the highly similar bovine microsomal isoenzyme in the oxidized form. The analysis of the elements of secondary structure is instructive in terms of their stability and of their occurrence in related structures, and of the capability of NMR and X-ray spectroscopy to observe them. Some detailed structural variations are noticed among the solved structures of the various isoenzymes and between solid and solution. The structural features in solution of the residues proposed to be involved in protein-protein recognition are found to be largely conserved with respect to the solid state.

关键词： cytochrome b(5) protein recognition solution structure secondary structure

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solution structure OF TURKEY OVOMUCOID 3RD DOMAIN AS DETERMINED FROM NUCLEAR-MAGNETIC-RESONANCE DATA

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JOURNAL OF MOLECULAR BIOLOGY 1994年第3期242卷 203-214页

作者： KREZEL, AM DARBA, P ROBERTSON, AD FEJZO, J MACURA, S MARKLEY, JL UNIV WISCONSIN COLL AGR & LIFE SCI DEPT BIOCHEM MADISON WI 53706 USA UNIV WISCONSIN DEPT BIOCHEM NATL MAGNET RESONANCE FACIL MADISON WI 53706 USA MAYO CLIN & MAYO FDN DEPT BIOCHEM & MOLEC BIOL ROCHESTER MN 55905 USA

The solution structure of the 56 amino acid residue turkey ovomucoid third domain was determined by n.m.r methods. Of the 661 distance constraints used in the calculations, 120 were determined by quadratic approximation of the cross-relaxation rates. The remaining constraints were crudely estimated from a more standard analysis of NOESY spectra. Additionally, 29 torsion angle constraints, 17 hydrogen bonds, and three disulfide bridges were used in the structure calculations. Stereospecific assignments were accomplished for 24 beta-methylene groups and six isopropyl methyl groups (43 % chiral assignments). The addition of more accurate distance constraints to the distance geometry/simulated annealing approach resulted in a significant reduction in the dispersion of calculated backbone torsion angles and root-mean-square deviations between structures. Detailed comparisons have been made between the n.m.r. structures of OMTKY3 and published X-ray structures of the same protein and of closely related avian ovomucoid third domains. The refinement with more accurate distance constraints reduced differences between families of the n.m.r. and the X-ray structures.

关键词： OMTIKY3 NMR solution structure PROTEIN PROTEINASE INHIBITOR

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solution structure of a novel ET_B receptor selective agonist ET1-21[Cys(Acm)^1,15, Aib^3,11, Leu⁷] by nuclear magnetic resonance spectroscopy and molecular modelling

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JOURNAL OF PEPTIDE RESEARCH 1999年第3期53卷 223-233页

作者： Hewage, CM Jiang, L Parkinson, JA Ramage, R Sadler, IH Univ Edinburgh Dept Chem Edinburgh EH9 3JJ Midlothian Scotland

The solution structure of a biologically active modified linear endothelin-l analogue, ET1-21[Cys(Acm)(1,15), Aib(3,11), Leu(7)]. has been determined for the first time by two-dimensional nuclear magnetic resonance spectroscopy in a methanol-d(3)/water solvent mixture. Out of approximately one hundred linear peptide analogues tested by biological assay, this peptide, together with a dozen others, showed significant ETB selective agonist activity. Here we report the solution structure of an ETB selective agonist of a full-length, synthetic linear endothelin analogue. The calculated structures indicate that the peptide adopts an alpha-helical conformation between residues Ser(5)-His(16), whilst both N- and C-termini show no preferred conformation. These results suggest that the disulphide bridges normally associated with endothelin and sarafotoxin peptides may not necessarily be important for either ETB receptor binding activity or the formation of a helical conformation in solution.

关键词： endothelin-1 ETB agonist molecular modelling NMR solution structure

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solution structure of ASPP2 n-terminal domain (N-ASPP2) reveals a ubiquitin-like fold

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JOURNAL OF MOLECULAR BIOLOGY 2007年第4期371卷 948-958页

作者： Tidow, Henning Andreeva, Antonina Rutherford, Trevor J. Fersht, Alan R. MRC Ctr Prot Engn Cambridge CB2 0QH England

Proteins of the ASPP family bind to p53 and regulate p53-mediated apoptosis. Two family members, ASPP1 and ASPP2, have pro-apoptotic functions while iASPP shows anti-apoptotic responses. However, both the mechanism of enhancement/repression of apoptosis and the molecular basis for their different responses remain unknown. To address the role of the N-termini of pro-apoptotic ASPP proteins, we solved the solution structure of N-ASPP2 (1-83) by NMR spectroscopy. The structure of this domain reveals a beta-Grasp ubiquitin-like fold. Our findings suggest a possible role for the N-termini of ASPP proteins in binding to other proteins in the apoptotic response network and thus mediating their selective pro-apoptotic function. (c) 2007 Elsevier Ltd. All rights reserved.

关键词： aSPP2 solution structure NMR ubiquitin-like beta-Grasp

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