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Protein Crystal Structure

Oliviero Carugo
Proteins are not static molecules but dynamic entities able to modify their structure for several reasons, from the necessity to recognize partners to the regulation of their thermodynamic stability. Conformational disorder is frequent in protein structures and atoms can have, in protein crystal structures, two or more alternative, equilibrium positions close to each other. Here, a set of protein crystal structures refined at very high resolution (1 Å or better) is examined to characterize the conformational disorder of the backbone atoms, which is not infrequent: about 15% of the protein backbone atoms are conformationally disordered and three quarters of them have been deposited with two or more equilibrium positions (most of the others were not detected in the electron density maps)...
December 4, 2018: Amino Acids
Sai Pooja Mahajan, Bunyarit Meksiriporn, Dujduan Waraho-Zhmayev, Kevin B Weyant, Ilkay Kocer, David C Butler, Anne Messer, Fernando A Escobedo, Matthew P DeLisa
Improving the affinity of protein-protein interactions is a challenging problem that is particularly important in the development of antibodies for diagnostic and clinical use. Here, we used structure-based computational methods to optimize the binding affinity of VH NAC1, a single-domain intracellular antibody (intrabody) from the camelid family that was selected for its specific binding to the nonamyloid component (NAC) of human α-synuclein (α-syn), a natively disordered protein, implicated in the pathogenesis of Parkinson's disease (PD) and related neurological disorders...
December 4, 2018: Scientific Reports
Sudarat Tharad, Öykü Üzülmez, Boonhiang Promdonkoy, José L Toca-Herrera
Cytolytic protein (Cyt) is a member of insecticidal proteins produced by Bacillus thuringiensis . Cyt protein has activity against insect cells and mammalian cells, which differ in lipid and cholesterol composition. This study presents the lipid binding behavior of Cyt2Aa2 protein on model membranes containing different levels of cholesterol content by combining Quartz Crystal Microbalance with Dissipation (QCM-D) and Atomic Force Microscopy (AFM). QCM-D results revealed that cholesterol enhances the binding rate of Cyt2Aa2 protein onto lipid bilayers...
November 30, 2018: International Journal of Molecular Sciences
Seiki Yageta, Hiroshi Imamura, Risa Shibuya, Shinya Honda
The N-linked glycan in immunoglobulin G is critical for the stability and function of the crystallizable fragment (Fc) region. Alteration of these protein properties upon the removal of the N-linked glycan has often been explained by the alteration of the CH 2 domain orientation in the Fc region. To confirm this hypothesis, we examined the small-angle X-ray scattering (SAXS) profile of the glycosylated Fc region (gFc) and aglycosylated Fc region (aFc) in solution. Conformational characteristics of the CH 2 domain orientation were validated by comparison with SAXS profiles theoretically calculated from multiple crystal structures of the Fc region with different CH 2 domain orientations...
December 4, 2018: MAbs
Jonas Dittrich, Denis Schmidt, Christopher Pfleger, Holger Gohlke
We present DrugScore2018, a new version of the knowledge-based scoring function DrugScore, which builds upon the same formalism used to derive DrugScore, but exploits a training data set of nearly 40,000 X-ray complex structures, a highly diverse and the by far largest dataset ever used for such an endeavour. About 2.5 times as many pair potentials than before now have a data basis required to yield smooth potentials, and pair potentials could now be derived for eight more atom types, including interactions involving halogen atoms and metal ions highly relevant for medicinal chemistry...
December 4, 2018: Journal of Chemical Information and Modeling
Alfredo J Guerra, Ou Zhang, Constance M E Bahr, My-Hang Huynh, James DelProposto, William C Brown, Zdzislaw Wawrzak, Nicole M Koropatkin, Vern B Carruthers
Intracellular pathogens must egress from the host cell to continue their infectious cycle. Apicomplexans are a phylum of intracellular protozoans that have evolved members of the membrane attack complex and perforin (MACPF) family of pore forming proteins to disrupt cellular membranes for traversing cells during tissue migration or egress from a replicative vacuole following intracellular reproduction. Previous work showed that the apicomplexan Toxoplasma gondii secretes a perforin-like protein (TgPLP1) that contains a C-terminal Domain (CTD) which is necessary for efficient parasite egress...
December 4, 2018: PLoS Pathogens
Meng S Choy, Nicolas Bolik-Coulon, Tara L Archuleta, Wolfgang Peti, Rebecca Page
Protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. The vast majority of regulators are intrinsically disordered proteins (IDPs) and bind PP1 via short linear motifs within their intrinsically disordered regions. One of the most ancient PP1 regulators is SDS22, a protein that is conserved from yeast to mammals. Sequence analysis of SDS22 revealed that it is a leucine-rich repeat (LRR) protein, suggesting that SDS22, unlike nearly every other known PP1 regulator, is not an IDP but instead is fully structured...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Satoshi Fukuhara, Takanori Nakane, Keitaro Yamashita, Ryohei Ishii, Ryuichiro Ishitani, Osamu Nureki
The type VI secretion system (T6SS) comprises needle-shaped multisubunit complexes that play a role in the microbial defense systems of Gram-negative bacteria. Some Gram-negative bacteria harboring a T6SS deliver toxic effector proteins into the cytoplasm or periplasm of competing bacteria in order to lyse and kill them. To avoid self-cell disruption, these bacteria have cognate immunity proteins that inhibit their toxic effector proteins. T6SS amidase effector protein 4 (Tae4) and T6SS amidase immunity protein 4 (Tai4) are a representative of the toxic effector-immunity pairs of the T6SS...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Arvind Kumar Gupta, Debashree Behera, Balasubramanian Gopal
The crystal structure of Mycobacterium tuberculosis high-temperature requirement A (HtrA) protein was determined at 1.83 Å resolution. This membrane-associated protease is essential for the survival of M. tuberculosis. The crystal structure reveals that interactions between the PDZ domain and the catalytic domain in HtrA lead to an inactive conformation. This finding is consistent with its proposed role as a regulatory protease that is conditionally activated upon appropriate environmental triggers. The structure provides a basis for directed studies to evaluate the role of this essential protein and the regulatory pathways that are influenced by this protease...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Saeid Karkehabadi, Henrik Hansson, Nils Egil Mikkelsen, Steve Kim, Thijs Kaper, Mats Sandgren, Mikael Gudmundsson
The glycoside hydrolase family 3 (GH3) β-glucosidases are a structurally diverse family of enzymes. Cel3A from Neurospora crassa (NcCel3A) belongs to a subfamily of key enzymes that are crucial for industrial biomass degradation. β-Glucosidases hydrolyse the β-1,4 bond at the nonreducing end of cellodextrins. The hydrolysis of cellobiose is of special importance as its accumulation inhibits other cellulases acting on crystalline cellulose. Here, the crystal structure of the biologically relevant dimeric form of NcCel3A is reported...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Rattanaporn Intuy, Takafumi Itoh, Wasana Suyotha, Junji Hayashi, Shigekazu Yano, Koki Makabe, Mamoru Wakayama, Takao Hibi
α-1,3-Glucanase hydrolyzes α-1,3-glucan, an insoluble linear α-1,3-linked homopolymer of glucose that is found in the extracellular polysaccharides produced by oral streptococci in dental plaque and in fungal cell walls. This enzyme could be of application in dental care and the development of fungal cell-wall lytic enzymes, but its three-dimensional structure has not been available to date. In this study, the recombinant catalytic domain of α-1,3-glucanase FH1 from Paenibacillus glycanilyticus FH11, which is classified into glycoside hydrolase family 87, was prepared using a Brevibacillus choshinensis expression system and purified in a soluble form...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Tzu Ping Ko, Chi Hung Huang, Shu Jung Lai, Yeh Chen
Undecaprenyl pyrophosphate (UPP) is an important carrier of the oligosaccharide component in peptidoglycan synthesis. Inhibition of UPP synthase (UPPS) may be an effective strategy in combating the pathogen Acinetobacter baumannii, which has evolved to be multidrug-resistant. Here, A. baumannii UPPS (AbUPPS) was cloned, expressed, purified and crystallized, and its structure was determined by X-ray diffraction. Each chain of the dimeric protein folds into a central β-sheet with several surrounding α-helices, including one at the C-terminus...
December 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Min Fey Chek, Ayaka Hiroe, Toshio Hakoshima, Kumar Sudesh, Seiichi Taguchi
Polyhydroxyalkanoates (PHAs) are biopolymers synthesized by a wide range of bacteria, which serve as a promising candidate in replacing some conventional petrochemical-based plastics. PHA synthase (PhaC) is the key enzyme in the polymerization of PHA, and the crystal structures were successfully determined using the catalytic domain of PhaC from Cupriavidus necator (PhaCCn -CAT) and Chromobacterium sp. USM2 (PhaCCs -CAT). Here, we review the beneficial mutations discovered in PhaCs from a structural perspective...
December 3, 2018: Applied Microbiology and Biotechnology
Yosuke Toyoda, Kazushi Morimoto, Ryoji Suno, Shoichiro Horita, Keitaro Yamashita, Kunio Hirata, Yusuke Sekiguchi, Satoshi Yasuda, Mitsunori Shiroishi, Tomoko Shimizu, Yuji Urushibata, Yuta Kajiwara, Tomoaki Inazumi, Yunhon Hotta, Hidetsugu Asada, Takanori Nakane, Yuki Shiimura, Tomoya Nakagita, Kyoshiro Tsuge, Suguru Yoshida, Tomoko Kuribara, Takamitsu Hosoya, Yukihiko Sugimoto, Norimichi Nomura, Miwa Sato, Takatsugu Hirokawa, Masahiro Kinoshita, Takeshi Murata, Kiyoshi Takayama, Masaki Yamamoto, Shuh Narumiya, So Iwata, Takuya Kobayashi
Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain...
December 3, 2018: Nature Chemical Biology
Kazushi Morimoto, Ryoji Suno, Yunhong Hotta, Keitaro Yamashita, Kunio Hirata, Masaki Yamamoto, Shuh Narumiya, So Iwata, Takuya Kobayashi
Prostanoids are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G-protein-coupled receptors (GPCRs). Here, we report the crystal structure of human prostaglandin (PG) E receptor subtype EP3 bound to endogenous ligand PGE2 at 2.90 Å resolution. The structure reveals important insights into the activation mechanism of prostanoid receptors and provides a molecular basis for the binding modes of endogenous ligands.
December 3, 2018: Nature Chemical Biology
Weihua Qiu, Ziao Fu, Guoyan G Xu, Robert A Grassucci, Yan Zhang, Joachim Frank, Wayne A Hendrickson, Youzhong Guo
Membrane proteins function in native cell membranes, but extraction into isolated particles is needed for many biochemical and structural analyses. Commonly used detergent-extraction methods destroy naturally associated lipid bilayers. Here, we devised a detergent-free method for preparing cell-membrane nanoparticles to study the multidrug exporter AcrB, by cryo-EM at 3.2-Å resolution. We discovered a remarkably well-organized lipid-bilayer structure associated with transmembrane domains of the AcrB trimer...
December 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Zi S D Toa, Jacob C Dean, Gregory D Scholes
The attribution of quantum beats observed in the time-resolved spectroscopy of photosynthetic light-harvesting antennae to nontrivial quantum coherences has sparked a flurry of research activity beginning a decade ago. Even though investigations into the functional aspects of photosynthetic light-harvesting were supported by X-ray crystal structures, the non-covalent interactions between pigments and their local protein environment that drive such function has yet to be comprehensively explored. Using symmetry-adapted perturbation theory (SAPT), we have comprehensively determined the magnitude and compositions of these non-covalent interactions involving light-harvesting chromophores in two quintessential photosynthetic pigment-protein complexes - peridinin chlorophyll-a protein (PCP) from dinoflagellate Amphidinium carterae and phycocyanin 645 (PC645) from cryptophyte Chroomonas mesostigmatica...
November 19, 2018: Journal of Photochemistry and Photobiology. B, Biology
J Kalervo Hiltunen, Alexander J Kastaniotis, Kaija J Autio, Guangyu Jiang, Zhijun Chen, Tuomo Glumoff
17β-Hydroxysteroid dehydrogenases (HSD17B) catalyze the oxidation/reduction of 17β-hydroxy/keto group in position C17 in C18- and C19 steroids. Most HSD17Bs are also catalytically active with substrates other than steroids. A subset of these enzymes is able to process thioesters of carboxylic acids. This group of enzymes includes HSD17B4, HSD17B8, HSD17B10 and HSD17B12, which execute reactions in intermediary metabolism, participating in peroxisomal β-oxidation of fatty acids, mitochondrial oxidation of 3R-hydroxyacyl-groups, breakdown of isoleucine and fatty acid chain elongation in endoplasmic reticulum...
November 30, 2018: Molecular and Cellular Endocrinology
Ramesh Chandra Halder, Cynthia Tran, Priti Prasad, Jing Wang, Dhiraj Nallapothula, Tatsuya Ishikawa, Meiying Wang, Dirk M Zajonc, Ram Raj Singh
Glycosphingolipids and glycerophospholipids bind CD1d. Glycosphingolipid-reactive invariant NKT-cells (iNKT) exhibit myriad immune effects, however, little is known about the functions of phospholipid-reactive T-cells (PLT). We report that the normal mouse immune repertoire contains αβ T-cells, which recognize self-glycerophospholipids such as phosphatidic acid (PA) in a CD1d-restricted manner and don't cross-react with iNKT-cell ligands. PA bound to CD1d in the absence of lipid transfer proteins. Upon in vivo priming, PA induced an expansion and activation of T-cells in Ag-specific manner...
December 3, 2018: European Journal of Immunology
Zhu Si, Jiayan Zhang, Sakar Shivakoti, Ivo Atanasov, Chang-Lu Tao, Wong H Hui, Kang Zhou, Xuekui Yu, Weike Li, Ming Luo, Guo-Qiang Bi, Z Hong Zhou
Human cytomegalovirus (HCMV) enters host by glycoprotein B (gB)-mediated membrane fusion upon receptor-binding to gH/gL-related complexes, causing devastating diseases such as birth defects. Although an X-ray crystal structure of the recombinant gB ectodomain at postfusion conformation is available, the structures of prefusion gB and its complex with gH/gL on the viral envelope remain elusive. Here, we demonstrate the utility of cryo electron tomography (cryoET) with energy filtering and the cutting-edge technologies of Volta phase plate (VPP) and direct electron-counting detection to capture metastable prefusion viral fusion proteins and report the structures of glycoproteins in the native environment of HCMV virions...
December 3, 2018: PLoS Pathogens
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