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Structure (v.13, #6)

Gemin 6 and 7 Lend a Hand to snRNP Assembly by Adelaine K.W. Leung; Kiyoshi Nagai (pp. 833-834).
A structure of the Gemin 6 and 7 heterodimer (Ma et al., [2005], this issue of Structure) suggests how the survival of motor neuron (SMN) complex might facilitate the assembly of snRNPs that play important roles in pre-mRNA splicing.

LOX-1 Unlocked by Tatsuya Sawamura (pp. 834-835).
The solution of the crystal structure of LOX-1, originally identified as the endothelial receptor for oxidized LDL (Sawamura et al., 1997), has been reported by the Tate (Ohki et al., 2005) and Boyington groups (Park et al., 2005).

Molecular Mastication Mechanics by Dmitry A. Kondrashov; George N. Phillips Jr. (pp. 836-837).
Computational prediction of global protein motion by Yang and Bahar (2005) (in this issue of Structure) suggests that enzymatic active sites tend to be placed near the hinges of the “jaws? of enzyme structures.

The Bacterial Helicase-Primase Interaction: A Common Structural/Functional Module by Panos Soultanas (pp. 839-844).
The lack of a high-resolution structure for the bacterial helicase-primase complex and the fragmented structural information for the individual proteins have been hindering our detailed understanding of this crucial binary protein interaction. Two new structures for the helicase-interacting domain of the bacterial primases from Escherichia coli and Bacillus stearothermophilus have recently been solved and both revealed a unique and surprising structural similarity to the amino-terminal domain of the helicase itself. In this minireview, the current data are discussed and important new structural and functional aspects of the helicase-primase interaction are highlighted. An attractive structural model with direct biological significance for the function of this complex and also for the development of new antibacterial compounds is examined.

Homage to Prof. M.G. Replacement: A Celebration of Structural Biology at Purdue University by Cele Abad-Zapatero (pp. 845-848).
On a glorious spring day in the American Midwest, friends, colleagues, collaborators, and alumni of Prof. M.G. Replacement gathered together at the campus of Purdue University, West Lafayette, Indiana to celebrate 40 years of structural biology and honor the man behind it all: M.G. Rossmann. The date also corresponded approximately to MGR’s 75th birthday. It was a memorable occasion for several reasons. An earlier meeting 10 years ago did also render homage to Michael (New Directions in Protein-Structure Relationships: Symposium in Honor of Professor M.G. Rossmann’s 65th Birthday, Purdue University, October 21, 1995), but on this occasion the symposium was much more encompassing of structural biology and had a more global character. A large number of featured speakers presented and discussed advances in vast areas of structural biology and came from the four corners of the world to share their work with the new generations of structural biologists currently being trained at Purdue University.

The α Helix Dipole: Screened Out? by Durba Sengupta; Raghu Nath Behera; Jeremy C. Smith; G. Matthias Ullmann (pp. 849-855).
Aligned α helix peptide dipoles sum to a “macroscopic? dipole parallel to the helix axis that has been implicated in protein folding and function. However, in aqueous solution the dipole is counteracted by an electrostatic reaction field generated by the solvent, and the strength of the helix dipole may reduce drastically from its value in vacuum. Here, using atomic-detail helix models and Poisson-Boltzmann continuum electrostatics calculations, the net effective dipole moment, μeff, is calculated. Some initially surprising results are found. Whereas in vacuum μeff increases with helix length, the opposite is found to be the case for transmembrane helices. In soluble proteins, μeff is found to vary strongly with the orientation and position of the helix relative to the aqueous medium. A set of rules is established to estimate of the strength of μeff from graphical inspection of protein structures.

Structural Genomics of Thermotoga maritima Proteins Shows that Contact Order Is a Major Determinant of Protein Thermostability by Marc Robinson-Rechavi; Adam Godzik (pp. 857-860).
Despite numerous studies, understanding the structural basis of protein stability in thermophilic organisms has remained elusive. One of the main reasons is the limited number of thermostable protein structures available for analysis, but also the difficulty in identifying relevant features to compare. Notably, an intuitive feeling of “compactness? of thermostable proteins has eluded quantification. With the unprecedented opportunity to assemble a data set for comparative analyses due to the recent advances in structural genomics, we can now revisit this issue and focus on experimentally determined structures of proteins from the hyperthermophilic bacterium Thermotoga maritima. We find that 73% of T. maritima proteins have higher contact order than their mesophilic homologs. Thus, contact order, a structural feature that was originally introduced to explain differences in folding rates of different protein families, is a significant parameter that can now be correlated with thermostability.

The Crystal Structure of a c-Src Complex in an Active Conformation Suggests Possible Steps in c-Src Activation by Sandra W. Cowan-Jacob; Gabriele Fendrich; Paul W. Manley; Wolfgang Jahnke; Doriano Fabbro; Janis Liebetanz; Thomas Meyer (pp. 861-871).
The regulation of the activity of Abl and Src family tyrosine kinases is mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1) domains. We have determined the crystal structure of an unphosphorylated form of c-Src in which the SH2 domain is not bound to the C-terminal tail. This results in an open structure where the kinase domain adopts an active conformation and the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR binding studies support the hypothesis that an N-terminal myristate could bind in this pocket, as observed for Abl, suggesting that c-Src may also be regulated by myristate binding. In addition, the structure contains a des-methyl analog of the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile.

Structural Dissection of ATP Turnover in the Prototypical GHL ATPase TopoVI by Kevin D. Corbett; James M. Berger (pp. 873-882).
GHL proteins are functionally diverse enzymes defined by the presence of a conserved ATPase domain that self-associates to trap substrate upon nucleotide binding. The structural states adopted by these enzymes during nucleotide hydrolysis and product release, and their consequences for enzyme catalysis, have remained unclear. Here, we have determined a complete structural map of the ATP turnover cycle for topoVI-B, the ATPase subunit of the archaeal GHL enzyme topoisomerase VI. With this ensemble of structures, we show that significant conformational changes in the subunit occur first upon ATP binding, and subsequently upon release of hydrolyzed Pi. Together, these data provide a structural framework for understanding the role of ATP hydrolysis in the type II topoisomerase reaction. Our results also suggest that the GHL ATPase module is a molecular switch in which ATP hydrolysis serves as a prerequisite but not a driving force for substrate-dependent structural transitions in the enzyme.

The Gemin6-Gemin7 Heterodimer from the Survival of Motor Neurons Complex Has an Sm Protein-like Structure by Yingli Ma; Jose Dostie; Gideon Dreyfuss; Gregory D. Van Duyne (pp. 883-892).
The survival of motor neurons (SMN) protein, product of the disease gene of the common neurodegenerative disease spinal muscular atrophy, is part of the large multiprotein “SMN complex.? The SMN complex functions as an assembly machine for small nuclear ribonucleoproteins (snRNPs)—the major components of the spliceosome. Here, we report the crystal structure of two components of the human SMN complex, Gemin6 and Gemin7. Although Gemin6 and Gemin7 have no significant sequence similarity with Sm proteins, both adopt canonical Sm folds. Moreover, Gemin6 and Gemin7 exist as a heterodimer, and interact with each other via an interface similar to that which mediates interactions among the Sm proteins. Together with binding experiments that show that the Gemin6/Gemin7 complex binds to Sm proteins, these findings provide a framework for considering how the SMN complex, with Gemin6 and Gemin7 as tools, might organize Sm proteins for formation of Sm rings on snRNA targets.

Coupling between Catalytic Site and Collective Dynamics: A Requirement for Mechanochemical Activity of Enzymes by Lee-Wei Yang; Ivet Bahar (pp. 893-904).
Growing evidence supports the view that enzymatic activity results from a subtle interplay between chemical kinetics and molecular motions. A systematic analysis is performed here to delineate the type and level of coupling between catalysis and conformational mechanics. The dynamics of a set of 98 enzymes representative of different EC classes are analyzed with the Gaussian network model (GNM) and compared with experimental data. In more than 70% of the examined enzymes, the global hinge centers predicted by the GNM are found to be colocalized with the catalytic sites experimentally identified. Low translational mobility (<7%) is observed for the catalytic residues, consistent with the fine-tuned design of enzymes to achieve precise mechanochemical activities. Ligand binding sites, while closely neighboring catalytic sites, enjoy a moderate flexibility to accommodate the ligand binding. These findings could serve as additionalcriteria for assessing drug binding residues and could lessen the computational burden of substrate docking searches.

Crystal Structure of Human Lectin-like, Oxidized Low-Density Lipoprotein Receptor 1 Ligand Binding Domain and Its Ligand Recognition Mode to OxLDL by Izuru Ohki; Tomoko Ishigaki; Takuji Oyama; Shigeru Matsunaga; Qiuhong Xie; Mayumi Ohnishi-Kameyama; Takashi Murata; Daisuke Tsuchiya; Sachiko Machida; Kousuke Morikawa; Shin-ichi Tate (pp. 905-917).
Lectin-like, oxidized low-density lipoprotein (LDL) receptor 1, LOX-1, is the major receptor for oxidized LDL (OxLDL) in endothelial cells. We have determined the crystal structure of the ligand binding domain of LOX-1, with a short stalk region connecting the domain to the membrane-spanning region, as a homodimer linked by an interchain disulfide bond. In vivo assays with LOX-1 mutants revealed that the “basic spine,? consisting of linearly aligned arginine residues spanning over the dimer surface, is responsible for ligand binding. Single amino acid substitution in the dimer interface caused a severe reduction in LOX-1 binding activity, suggesting that the correct dimer arrangement is crucial for binding to OxLDL. Based on the LDL model structure, possible binding modes of LOX-1 to OxLDL are proposed.

AbrB-like Transcription Factors Assume a Swapped Hairpin Fold that Is Evolutionarily Related to Double-Psi β Barrels by Murray Coles; Sergej Djuranovic; Johannes Sding; Tancred Frickey; Kristin Koretke; Vincent Truffault; Jrg Martin; Andrei N. Lupas (pp. 919-928).
AbrB is a key transition-state regulator of Bacillus subtilis. Based on the conservation of a βαβ structural unit, we proposed a β barrel fold for its DNA binding domain, similar to, but topologically distinct from, double-psi β barrels. However, the NMR structure revealed a novel fold, the “looped-hinge helix.? To understand this discrepancy, we undertook a bioinformatics study of AbrB and its homologs; these form a large superfamily, which includes SpoVT, PrlF, MraZ, addiction module antidotes (PemI, MazE), plasmid maintenance proteins (VagC, VapB), and archaeal PhoU homologs. MazE and MraZ form swapped-hairpin β barrels. We therefore reexamined the fold of AbrB by NMR spectroscopy and found that it also forms a swapped-hairpin barrel. The conservation of the core βαβ element supports a common evolutionary origin for swapped-hairpin and double-psi barrels, which we group into a higher-order class, the cradle-loop barrels, based on the peculiar shape of their ligand binding site.

Structure and Mechanism of ArnA: Conformational Change Implies Ordered Dehydrogenase Mechanism in Key Enzyme for Polymyxin Resistance by Petia Z. Gatzeva-Topalova; Andrew P. May; Marcelo C. Sousa (pp. 929-942).
The modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) allows gram-negative bacteria to resist the antimicrobial activity of cationic antimicrobial peptides and antibiotics such as polymyxin. ArnA is the first enzyme specific to the lipid A-Ara4N pathway. It contains two functionally and physically separable domains: a dehydrogenase domain (ArnA_DH) catalyzing the NAD+-dependent oxidative decarboxylation of UDP-Glucuronic acid (UDP-GlcA), and a transformylase domain that formylates UDP-Ara4N. Here, we describe the crystal structure of the full-length bifunctional ArnA with UDP-GlcA and ATP bound to the dehydrogenase domain. Binding of UDP-GlcA triggers a 17 conformational change in ArnA_DH that opens the NAD+ binding site while trapping UDP-GlcA. We propose an ordered mechanism of substrate binding and product release. Mutation of residues R619 and S433 demonstrates their importance in catalysis and suggests that R619 functions as a general acid in catalysis. The proposed mechanism for ArnA_DH has important implications for the design of selective inhibitors.
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