The CCPN project: an interim report on a data model for the NMR community

Fogh, Rasmus H.; Ionides, John; Ulrich, Eldon L.; Boucher, Wayne; Vranken, Wim; Linge, Jens P.; Habeck, Michael; Rieping, Wolfgang; Bhat, Talapady N.; Westbrook, John D.; Henrick, Kim; Gilliland, Gary L.; Berman, Helen M.; Thornton, Janet M.; Nilges, Michaël; Markley, John L.; Laue, Ernest D.

doi:10.1038/nsb0602-416

Cited by 120 publications

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“…These spectra supplemented the 15 N-edited NOESY-HSQC and TOCSY-HSQC spectra gained previously (10). All spectra were processed and viewed with NMRPipe (16) and CcpN Analysis (17,18 15 N]-labeled rat FAS apoACP. In this sample both the hexanoyl group and phosphopantetheine side arm are not enriched with 13 C or 15 N. Structure Calculation-Peak and shift lists were assigned manually using standard sequential assignment methods.…”

Section: Methodsmentioning

confidence: 99%

A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains

Płoskoń¹,

Arthur

Evans

et al. 2008

Journal of Biological Chemistry

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The synthases that produce fatty acids in mammals (FASs) are arranged as large multidomain polypeptides. The growing fatty acid chain is bound covalently during chain elongation and reduction to the acyl carrier protein (ACP) domain that is then able to access each catalytic site. In this work we report the highresolution nuclear magnetic resonance (NMR) solution structure of the isolated rat fatty acid synthase apoACP domain. Fatty acid biosynthesis in mammals is important not only for energy homeostasis and development but also as a potential target for the treatment of obesity (1) and cancer (2). Type I fatty acid synthases (FASs) 3 that catalyze the biosynthesis of fatty acids in mammals, utilize simple acyl units, bound to the phosphopantetheine arm of a holo acyl carrier protein (ACP) domain, for chain initiation and elongation. The recent elucidation of the low resolution structure of the mammalian FAS by x-ray crystallography (3) has provided key structural and mechanistic insights into this important enzyme. Although the resolution of the crystal is insufficient to discern the backbone and side chains, the electron density has permitted the authors to propose a model based on the structures of individual domains and homologous enzymes. The authors have proposed a "head to head" dimeric model that comprises a central core consisting of the enol-reductase, dehydratase (DH), and ketosynthase with the malonyl transferase and ketoreductase domains being located peripherally. Dimerization occurs through association of the KS domains. Notable absences in the crystal structure are the locations of the peripheral ACP and thioesterase domains, suggesting that the positions of the ACP and thioesterase domains are relatively mobile compared with the core of the FAS. In comparison, bacterial Type II FASs consist of discrete monofunctional proteins (4). Structural studies of the Type II FAS ACP components are particularly well developed and have revealed the structural basis of acyl chain binding and the phenomenon of conformational switching. The crystal structures of Escherichia coli FAS butyryl (5), hexanoyl-, heptanoyl-, and decanoyl-ACPs (6) and nuclear magnetic resonance (NMR) structures of spinach FAS decanoyl-and stearoyl-ACPs have been reported (7). These structures reveal that during fatty acid biosynthesis, fully saturated acyl chains are sequestered within a central cavity in the ACP formed through conformational changes in the protein. The fatty acid chain is sequestered within the hydrophobic core of the ACP perhaps to protect the thioester moiety from hydrolysis. Binding of the acyl chain also influences the dynamics of the ACPs. Spinach FAS holo-ACP exists in equilibrium between a folded and largely disordered form, however, upon acylation this equilibrium is shifted toward the folded form. At present the physiological role of switching of this, and other ACPs, is unknown (8, 9). It has been suggested that switching confers allosteric regulation of the ACP, whereby its interaction with other enzymes...

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Section: Methodsmentioning

confidence: 99%

A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains

Płoskoń¹,

Arthur

Evans

et al. 2008

Journal of Biological Chemistry

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“…There were no distance violations greater than 0.2 Å and no dihedral violations greater than 5°. The CYANA-generated distance and angle restraints were converted into the CNS format in CCPN (23). The structure for the non-standard amino acid linker was generated and energy-minimized in PRODRG2 (24).…”

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confidence: 99%

Solution Structure of a Hydrocarbon Stapled Peptide Inhibitor in Complex with Monomeric C-terminal Domain of HIV-1 Capsid

Bhattacharya

Zhang

Debnath

et al. 2008

Journal of Biological Chemistry

105

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The human immunodeficiency virus type 1 (HIV-1) capsid protein plays a critical role in virus core particle assembly and is an important target for novel therapeutic strategies. In a previous study, we characterized the binding affinity of a hydrocarbon stapled helical peptide, NYAD-1, for the capsid protein (K d ϳ 1 M) and demonstrated its ability to penetrate the cell membrane (Zhang, H., Zhao, Q., Bhattacharya, S., Waheed, A. A., Tong, X., Hong, A., Heck, S., Goger, M., Cowburn, D., Freed, E. O., and Debnath, A. K. (2008) J. Mol. Biol. 378, 565-580). In cell-based assays, NYAD-1 colocalized with the Gag polyprotein during traffic to the plasma membrane and disrupted the formation of mature and immature virus particles in vitro systems. Here, we complement the cellular and biochemical data with structural characterization of the interactions between the capsid and a soluble peptide analogue, NYAD-13. Solution NMR methods were used to determine a high resolution structure of the complex between the inhibitor and a monomeric form of the C-terminal domain of the capsid protein (mCA-CTD). The intermolecular interactions are mediated by the packing of hydrophobic side chains at the buried interface and unperturbed by the presence of the olefinic chain on the solventexposed surface of the peptide. The results of the structural analysis provide valuable insight into the determinants for high affinity and selective inhibitors for HIV-1 particle assembly.Worldwide 30 million people are infected with human immunodeficiency virus type 1 (HIV-1), 2 and it has claimed more lives than some of the deadliest epidemics in human history. HIV-1 belongs to the retroviral family, and significant progress made in understanding its life cycle has fueled the development of diverse therapeutic strategies. Important targets for intervention include inhibiting the fusion of the virus at the surface of CD4 ϩ T cells, reverse transcription of the viral RNA, and processing of the gag polyprotein by the HIV-1 protease (1). However, none of these treatment strategies has proven to be fully effective against the rapid emergence of drug-resistant variants of the virus.As we gain further insight into the structural biology of the virus particle itself and the mechanism of its assembly from the gag polyprotein, the latter has emerged as an important new target for drug development (2). The newly synthesized gag protein migrates to the inner surface of the cell membrane, where it buds into an immature particle that encapsulates the genomic material and important viral proteins. Subsequent proteolytic cleavage of the gag protein into the matrix protein, capsid, and nucleocapsid protein lead to repacking of the core and the formation of the mature virus particle. The interactions involving the capsid protein play a crucial role in the formation of the virus core particle with the correct morphology and are an important target for disrupting the assembly step.The dimeric capsid protein consists of N-and C-terminal domains that are flexibly linked in...

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“…Similarly, the development of numerous methods to deal with all aspects of biomolecular NMR has lead to the creation of a collaborative project: the Collaborative Computing Project for NMR (CCPN) which proposed a general data model [227,228] permitting to handle all NMR objects from NMR raw data up to NMR structures.…”

Section: Data Model Databasesmentioning

confidence: 99%

Quantitative Analysis of Biomolecular NMR Spectra: A Prerequisite for the Determination of the Structure and Dynamics of Biomolecules

Malliavin

2006

COC

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Nuclear Magnetic Resonance (NMR) became during the two last decades an important method for biomolecular structure determination. NMR permits to study biomolecules in solution and gives access to the molecular flexibility at atomic level on a complete structure: in that respect, it is occupying a unique place i n structural biology. During the first years of its development, NMR was trying to meet the requirements previously defined in X-ray crystallography. But, NMR then started to determine its own criteria for the definition of a structure. Indeed, the atomic coordinates of an NMR structure are calculated using restraints on geometrical parameters (angles and distances) of the structure, which are only indirectly related to atom positions: in that respect, NMR and X-ray crystallography are very different. The indirect relation between the NMR measurements and the molecular structure and dynamics makes critical the precision and the interpretation of the NMR parameters and the development of quantitative analysis methods. The methods published since 1997 for liquid-NMR of proteins are reviewed here. First, methods for structure determination are presented, as well as methods for spectral assignment and for structure quality assessment. Second, the quantitative analysis of structure mobility i s reviewed.

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The CCPN project: an interim report on a data model for the NMR community

Abstract: A recent workshop discusses the progress toward integrating NMR data into a unifying data model.

Cited by 120 publications

References 0 publications

A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains

A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains

Solution Structure of a Hydrocarbon Stapled Peptide Inhibitor in Complex with Monomeric C-terminal Domain of HIV-1 Capsid

Quantitative Analysis of Biomolecular NMR Spectra: A Prerequisite for the Determination of the Structure and Dynamics of Biomolecules

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