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Membrane protein crystal structure

Tamas Yelland, Snezana Djordjevic
Neuropilins (NRPs) are single-pass transmembrane receptors involved in several signaling pathways that regulate key physiological processes such as vascular morphogenesis and axon guidance. The MAM domain of NRP, which has previously been implicated in receptor multimerization, was the only portion of the ectopic domain of the NRPs for which the structure, until now, has been elusive. Using site-directed mutagenesis in the linker region preceding the MAM domain we generated a protein construct amenable to crystallization...
October 3, 2016: Structure
Trent Conroy, Madhura Manohar, Yu Gong, Shane M Wilkinson, Michael Webster, Brian P Lieberman, Samuel D Banister, Tristan A Reekie, Robert H Mach, Louis M Rendina, Michael Kassiou
The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups...
October 4, 2016: Organic & Biomolecular Chemistry
Zhijie Li, Sayan Chakraborty, Guozhou Xu
Does not respond to nucleotides 1 (DORN1) has recently been identified as the first membrane-integral plant ATP receptor, which is required for ATP-induced calcium response, mitogen-activated protein kinase activation and defense responses in Arabidopsis thaliana. In order to understand DORN1-mediated ATP sensing and signal transduction, crystallization and preliminary X-ray studies were conducted on the extracellular domain of DORN1 (atDORN1-ECD) and that of an orthologous protein, Camelina sativa lectin receptor kinase I...
October 1, 2016: Acta Crystallographica. Section F, Structural Biology Communications
Dongdi Li, Ruth Moorman, Thomas Vanhercke, James Petrie, Surinder Singh, Colin J Jackson
Membrane fatty acid desaturases are a diverse superfamily of enzymes that catalyze the introduction of double bonds into fatty acids. They are essential in a range of metabolic processes, such as the production of omega-3 fatty acids. However, our structure-function understanding of this superfamily is still developing and their range of activities and substrate specificities are broad, and often overlapping, which has made their systematic characterization challenging. A central issue with characterizing these proteins has been the lack of a structural model, which has been overcome with the recent publication of the crystal structures of two mammalian fatty acid desaturases...
2016: Computational and Structural Biotechnology Journal
Luana G M Ferrara, Gregor D Wallat, Lucile Moynié, Naresh N Dhanasekar, Soumeya Aliouane, Silvia Acosta-Gutiérrez, Jean-Marie Pagès, Jean-Michel Bolla, Mathias Winterhalter, Matteo Ceccarelli, James H Naismith
The Gram-negative organism Campylobacter jejuni is the major cause of food poisoning. Unlike Escherichia coli, which has two major porins, OmpC and OmpF, C. jejuni has one, termed major outer membrane protein (MOMP) through which nutrients and antibiotics transit. We report the 2.1-Å crystal structure of C. jejuni MOMP expressed in E. coli and a lower resolution but otherwise identical structure purified directly from C. jejuni. The 2.1-Å resolution structure of recombinant MOMP showed that although the protein has timeric arrangement similar to OmpC, it is an 18-stranded, not 16-stranded, β-barrel...
September 30, 2016: Journal of Molecular Biology
Alexei Gorelik, Leonhard X Heinz, Katalin Illes, Giulio Superti-Furga, Bhushan Nagar
The enzyme acid sphingomyelinase-like phosphodiesterase 3B (SMPDL3B) was shown to act as a negative regulator of innate immune signaling, affecting cellular lipid composition and membrane fluidity. Furthermore, several reports identified this enzyme as an off-target of the therapeutic antibody rituximab, with implications in kidney disorders. However, structural information for this protein is lacking. Here we present the high-resolution crystal structure of murine SMPDL3B which reveals a substrate binding site strikingly different from its paralogs...
September 28, 2016: Journal of Biological Chemistry
Le Thi My Le, Wonchull Kang, Ji-Yun Kim, Oanh Thi Tu Le, Sang Yoon Lee, Jin Kuk Yang
The hexameric ATPase p97 has been implicated in diverse cellular processes through interactions with many different adaptor proteins at its N-terminal domain. Among these, the Ufd1-Npl4 heterodimer is a major adaptor, and the p97-Ufd1-Npl4 complex plays an essential role in endoplasmic reticulum-associated degradation (ERAD), acting as a segregase that translocates the ubiquitinated client protein from the ER membrane into the cytosol for proteasomal degradation. We determined the crystal structure of the complex of the N-terminal domain of p97 and the SHP box of Ufd1 at a resolution of 1...
2016: PloS One
Andrii Ishchenko, Vadim Cherezov, Wei Liu
Membrane proteins (MPs) are essential components of cellular membranes and primary drug targets. Rational drug design relies on precise structural information, typically obtained by crystallography; however MPs are difficult to crystallize. Recent progress in MP structural determination has benefited greatly from the development of lipidic cubic phase (LCP) crystallization methods, which typically yield well-diffracting, but often small crystals that suffer from radiation damage during traditional crystallographic data collection at synchrotron sources...
2016: Journal of Visualized Experiments: JoVE
Pradeep Sathyanarayana, Rajat Desikan, K Ganapathy Ayappa, Sandhya S Visweswariah
Pore-forming toxins (PFTs) bind to cell membranes and form nanoscale pores that allow leakage of cellular components, resulting in cell death. The water-soluble, monomeric form of these toxins shows a dramatic conformational change during pore formation, as exemplified by crystal structures of the monomer and functional pore of cytolysin A (ClyA). The solvent-exposed, C-terminal residues of the protein are essential for activity, but the mechanism by which this region regulates pore formation remains unknown...
October 13, 2016: Biochemistry
James Barber
About 3 billion years ago an enzyme emerged which would dramatically change the chemical composition of our planet and set in motion an unprecedented explosion in biological activity. This enzyme used solar energy to power the thermodynamically and chemically demanding reaction of water splitting. In so doing it provided biology with an unlimited supply of reducing equivalents needed to convert carbon dioxide into the organic molecules of life while at the same time produced oxygen to transform our planetary atmosphere from an anaerobic to an aerobic state...
January 2016: Quarterly Reviews of Biophysics
Linlin Zhao, Shuqing Wang, Changqing Run, Bo OuYang, James J Chou
Many membrane proteins bind specifically to lipids as an integral component of their structures. The ability of detergents to support lipid binding is thus an important consideration when solubilizing membrane proteins for structural studies. In particular, the zwitterionic phosphocholine (PC)-based detergents, which have been widely used in solution NMR studies of channels and transporters, are controversial because of their strong solubilization power and thus perceived as more denaturing than nonionic detergents such as the maltosides...
September 27, 2016: Biochemistry
Julian L Klosowiak, Sungjin Park, Kyle P Smith, Michael E French, Pamela J Focia, Douglas M Freymann, Sarah E Rice
Hereditary Parkinson's disease is commonly caused by mutations in the protein kinase PINK1 or the E3 ubiquitin ligase Parkin, which function together to eliminate damaged mitochondria. PINK1 phosphorylates both Parkin and ubiquitin to stimulate ubiquitination of dozens of proteins on the surface of the outer mitochondrial membrane. However, the mechanisms by which Parkin recognizes specific proteins for modification remain largely unexplored. Here, we show that the C-terminal GTPase (cGTPase) of the Parkin primary substrate human Miro is necessary and sufficient for efficient ubiquitination...
2016: Scientific Reports
Daniil M Prigozhin, Kadamba G Papavinasasundaram, Christina E Baer, Kenan C Murphy, Alisa Moskaleva, Tony Y Chen, Tom Alber, Christopher M Sassetti
Monitoring the environment with serine/threonine protein kinases is critical for growth and survival of Mycobacterium tuberculosis, a devastating human pathogen. Protein Kinase B (PknB) is a trans-membrane serine/threonine protein kinase that acts as an essential regulator of mycobacterial growth and division. The PknB extracellular domain (ECD) consists of four repeats homologous to penicillin-binding protein and serine/threonine kinase associated (PASTA) domains, and binds fragments of peptidoglycan. These properties suggest that PknB activity is modulated by ECD binding to peptidoglycan substructures, however the molecular mechanisms underpinning PknB regulation remain unclear...
September 6, 2016: Journal of Biological Chemistry
Yayoi Nomura, Yumi Sato, Ryoji Suno, Shoichiro Horita, So Iwata, Norimichi Nomura
Fv antibody fragments have been used as co-crystallization partners in structural biology, particularly in membrane protein crystallography. However, there are inherent technical issues associated with the large-scale production of soluble, functional Fv fragments through conventional methods in various expression systems. To circumvent these problems, we developed a new method, in which a single synthetic polyprotein consisting of a variable light (VL ) domain, an intervening removable affinity tag (iRAT), and a variable heavy (VH ) domain is expressed by a Gram-positive bacterial secretion system...
September 6, 2016: Protein Science: a Publication of the Protein Society
Kristian Parey, Alistair J Fielding, Matthias Sörgel, Reinhard Rachel, Harald Huber, Christine Ziegler, Chitra Rajendran
The Crenarchaeon Ignicoccus hospitalis lives in symbiosis with Nanoarchaeum equitans providing essential cell components and nutrients to its symbiont. Ignicoccus hospitalis shows an intriguing morphology that points towards an evolutionary role in driving compartmentalization. Therefore, the bioenergetics of this archaeal host-symbiont system remains a pressing question. To date, the only electron acceptor described for I. hospitalis is elemental sulfur, but the organism comprises genes that encode for enzymes involved in nitrogen metabolism, e...
September 1, 2016: FEBS Journal
Xiaoying Xu, Hao Song, Jianxun Qi, Yuqian Liu, Haiyuan Wang, Chao Su, Yi Shi, George F Gao
The association of Zika virus (ZIKV) infections with microcephaly and neurological diseases has highlighted an emerging public health concern. Here, we report the crystal structure of the full-length ZIKV nonstructural protein 1 (NS1), a major host-interaction molecule that functions in flaviviral replication, pathogenesis, and immune evasion. Of note, a long intertwined loop is observed in the wing domain of ZIKV NS1, and forms a hydrophobic "spike", which can contribute to cellular membrane association. For different flaviviruses, the amino acid sequences of the "spike" are variable but their common characteristic is either hydrophobic or positively charged, which is a beneficial feature for membrane binding...
August 30, 2016: EMBO Journal
Sayan Gupta, Jun Feng, Leanne Jade G Chan, Christopher J Petzold, Corie Y Ralston
The vast majority of biomolecular processes are controlled or facilitated by water interactions. In enzymes, regulatory proteins, membrane-bound receptors and ion-channels, water bound to functionally important residues creates hydrogen-bonding networks that underlie the mechanism of action of the macromolecule. High-resolution X-ray structures are often difficult to obtain with many of these classes of proteins because sample conditions, such as the necessity of detergents, often impede crystallization. Other biophysical techniques such as neutron scattering, nuclear magnetic resonance and Fourier transform infrared spectroscopy are useful for studying internal water, though each has its own advantages and drawbacks, and often a hybrid approach is required to address important biological problems associated with protein-water interactions...
September 1, 2016: Journal of Synchrotron Radiation
Eleonora Margheritis, Beatrice Castellani, Paola Magotti, Sara Peruzzi, Elisa Romeo, Francesca Natali, Serena Mostarda, Antimo Gioiello, Daniele Piomelli, Gianpiero Garau
The membrane-associated enzyme NAPE-PLD (N-acyl phosphatidylethanolamine specific-phospholipase D) generates the endogenous cannabinoid arachidonylethanolamide and other lipid signaling amides, including oleoylethanolamide and palmitoylethanolamide. These bioactive molecules play important roles in several physiological pathways including stress and pain response, appetite and lifespan. Recently, we reported the crystal structure of human NAPE-PLD and discovered specific binding sites for the bile acid deoxycholic acid...
August 29, 2016: ACS Chemical Biology
Lan Zhu, Uwe Weierstall, Vadim Cherezov, Wei Liu
Membrane proteins, including G protein-coupled receptors (GPCRs), constitute the most important drug targets. The increasing number of targets requires new structural information, which has proven tremendously challenging due to the difficulties in growing diffraction-quality crystals. Recent developments of serial femtosecond crystallography at X-ray free electron lasers combined with the use of membrane-mimetic gel-like matrix of lipidic cubic phase (LCP-SFX) for crystal growth and delivery hold significant promise to accelerate structural studies of membrane proteins...
2016: Advances in Experimental Medicine and Biology
Kathrin Jaeger, Florian Dworkowski, Przemyslaw Nogly, Christopher Milne, Meitian Wang, Joerg Standfuss
Serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs) is a powerful method to determine high-resolution structures of pharmaceutically relevant membrane proteins. Recently, the technology has been adapted to carry out serial millisecond crystallography (SMX) at synchrotron sources, where beamtime is more abundant. In an injector-based approach, crystals grown in lipidic cubic phase (LCP) or embedded in viscous medium are delivered directly into the unattenuated beam of a microfocus beamline...
2016: Advances in Experimental Medicine and Biology
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