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https://www.readbyqxmd.com/read/28712805/direct-spectroscopic-detection-of-atp-turnover-reveals-mechanistic-divergence-of-abc-exporters
#1
Alberto Collauto, Smriti Mishra, Aleksei Litvinov, Hassane S Mchaourab, Daniella Goldfarb
We have applied high-field (W-band) pulse electron-nuclear double resonance (ENDOR) and electron-electron double resonance (ELDOR)-detected nuclear magnetic resonance (EDNMR) to characterize the coordination sphere of the Mn(2+) co-factor in the nucleotide binding sites (NBSs) of ABC transporters. MsbA and BmrCD are two efflux transporters hypothesized to represent divergent catalytic mechanisms. Our results reveal distinct coordination of Mn(2+) to ATP and transporter residues in the consensus and degenerate NBSs of BmrCD...
July 13, 2017: Structure
https://www.readbyqxmd.com/read/28712807/snx16-regulates-the-recycling-of-e-cadherin-through-a-unique-mechanism-of-coordinated-membrane-and-cargo-binding
#2
Jinxin Xu, Leilei Zhang, Yinghua Ye, Yongli Shan, Chanjuan Wan, Junfeng Wang, Duanqing Pei, Xiaodong Shu, Jinsong Liu
E-Cadherin is a major component of adherens junctions on cell surfaces. SNX16 is a unique member of sorting nexins that contains a coiled-coil (CC) domain downstream of the PX domain. We report here that SNX16 regulates the recycling trafficking of E-cadherin. We solved the crystal structure of PX-CC unit of SNX16 and revealed a unique shear shaped homodimer. We identified a novel PI3P binding pocket in SNX16 that consists of both the PX and the CC domains. Surprisingly, we showed that the PPII/α2 loop, which is generally regarded as a membrane insertion loop in PX family proteins, is involved in the E-cadherin binding with SNX16...
July 11, 2017: Structure
https://www.readbyqxmd.com/read/28712809/near-atomic-resolution-structure-of-a-plant-geminivirus-determined-by-electron-cryomicroscopy
#3
Katharina Hipp, Clemens Grimm, Holger Jeske, Bettina Böttcher
African cassava mosaic virus is a whitefly-transmitted geminivirus which forms unique twin particles of incomplete icosahedra that are joined at five-fold vertices, building an unusual waist. How its 22 capsomers interact within a half-capsid or across the waist is unknown thus far. Using electron cryo-microscopy and image processing, we determined the virion structure with a resolution of 4.2 Å and built an atomic model for its capsid protein. The inter-capsomer contacts mediated by the flexible N termini and loop regions differed within the half-capsids and at the waist, explaining partly the unusual twin structure...
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28712808/structural-insight-into-the-activation-of-pkni-kinase-from-m-%C3%A2-tuberculosis-via-dimerization-of-the-extracellular-sensor-domain
#4
Qiaoling Yan, Dunquan Jiang, Lanfang Qian, Qingqing Zhang, Wei Zhang, Weihong Zhou, Kaixia Mi, Luke Guddat, Haitao Yang, Zihe Rao
Protein kinases play central roles in the survival of Mycobacterium tuberculosis within host. Here we report the individual high-resolution crystal structures of the sensor domain (in both monomer and dimer forms) and the kinase domain of PknI, a transmembrane protein member of the serine/threonine protein kinases (STPKs) family. PknI is the first STPK identified whose sensor domain exists in a monomer-dimer equilibrium. Inspection of the two structures of the sensor domain (PknI_SD) revealed conformational changes upon dimerization, with an arm region of critical importance for dimer formation identified...
July 4, 2017: Structure
https://www.readbyqxmd.com/read/28712810/conformational-heterogeneity-in-the-activation-mechanism-of-bax
#5
C Ashley Barnes, Pushpa Mishra, James L Baber, Marie-Paule Strub, Nico Tjandra
Bax is known for its pro-apoptotic role within the mitochondrial pathway of apoptosis. However, the mechanism for transitioning Bax from cytosolic to membrane-bound oligomer remains elusive. Previous nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) studies defined monomeric Bax as conformationally homogeneous. Yet it has recently been proposed that monomeric Bax exists in equilibrium with a minor state that is distinctly different from its NMR structure. Here, we revisited the structural analysis of Bax using methods uniquely suited for unveiling "invisible" states of proteins, namely, NMR paramagnetic relaxation enhancements and EPR double electron-electron resonance (DEER)...
July 3, 2017: Structure
https://www.readbyqxmd.com/read/28712806/structures-of-human-a1-and-a2a-adenosine-receptors-with-xanthines-reveal-determinants-of-selectivity
#6
Robert K Y Cheng, Elena Segala, Nathan Robertson, Francesca Deflorian, Andrew S Doré, James C Errey, Cédric Fiez-Vandal, Fiona H Marshall, Robert M Cooke
The adenosine A1 and A2A receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 Å resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2...
July 3, 2017: Structure
https://www.readbyqxmd.com/read/28689969/ancestral-reconstruction-approach-to-acetylcholine-receptor-structure-and-function
#7
Jethro E Prinston, Johnathon R Emlaw, Mathieu F Dextraze, Christian J G Tessier, F Javier Pérez-Areales, Melissa S McNulty, Corrie J B daCosta
Acetylcholine receptors (AChRs) are members of a superfamily of proteins called pentameric ligand-gated ion channels, which are found in almost all forms of life and thus have a rich evolutionary history. Muscle-type AChRs are heteropentameric complexes assembled from four related subunits (α, β, δ, and ɛ). Here we reconstruct the amino acid sequence of a β subunit ancestor shared by humans and cartilaginous fishes (i.e., Torpedo). Then, by resurrecting this ancestral β subunit and co-expressing it with human α, δ, and ɛ subunits, we show that despite 132 substitutions, the ancestral subunit is capable of forming human/ancestral hybrid AChRs...
June 30, 2017: Structure
https://www.readbyqxmd.com/read/28689970/structural-dynamics-of-zika-virus-ns2b-ns3-protease-binding-to-dipeptide-inhibitors
#8
Yan Li, Zhenzhen Zhang, Wint Wint Phoo, Ying Ru Loh, Weiling Wang, Shuang Liu, Ming Wei Chen, Alvin W Hung, Thomas H Keller, Dahai Luo, CongBao Kang
The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser(135) of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution...
June 23, 2017: Structure
https://www.readbyqxmd.com/read/28689968/the-ribosomal-protein-ul22-modulates-the-shape-of-the-protein-exit-tunnel
#9
Itai Wekselman, Ella Zimmerman, Chen Davidovich, Matthew Belousoff, Donna Matzov, Miri Krupkin, Haim Rozenberg, Anat Bashan, Gilgi Friedlander, Jette Kjeldgaard, Hanne Ingmer, Lasse Lindahl, Janice M Zengel, Ada Yonath
Erythromycin is a clinically useful antibiotic that binds to an rRNA pocket in the ribosomal exit tunnel. Commonly, resistance to erythromycin is acquired by alterations of rRNA nucleotides that interact with the drug. Mutations in the β hairpin of ribosomal protein uL22, which is rather distal to the erythromycin binding site, also generate resistance to the antibiotic. We have determined the crystal structure of the large ribosomal subunit from Deinococcus radiodurans with a three amino acid insertion within the β hairpin of uL22 that renders resistance to erythromycin...
June 21, 2017: Structure
https://www.readbyqxmd.com/read/28669634/structure-of-phytoene-desaturase-provides-insights-into-herbicide-binding-and-reaction-mechanisms-involved-in-carotene-desaturation
#10
Anton Brausemann, Sandra Gemmecker, Julian Koschmieder, Sandro Ghisla, Peter Beyer, Oliver Einsle
Cyanobacteria and plants synthesize carotenoids via a poly-cis pathway starting with phytoene, a membrane-bound C40 hydrocarbon. Phytoene desaturase (PDS) introduces two double bonds and concomitantly isomerizes two neighboring double bonds from trans to cis. PDS assembles into homo-tetramers that interact monotopically with membranes. A long hydrophobic tunnel is proposed to function in the sequential binding of phytoene and the electron acceptor plastoquinone. The herbicidal inhibitor norflurazon binds at a plastoquinone site thereby blocking reoxidation of FADred...
June 21, 2017: Structure
https://www.readbyqxmd.com/read/28669633/the-n-terminal-region-of-fibrillin-1-mediates-a-bipartite-interaction-with-ltbp1
#11
Ian B Robertson, Hans F Dias, Isabelle H Osuch, Edward D Lowe, Sacha A Jensen, Christina Redfield, Penny A Handford
Fibrillin-1 (FBN1) mutations associated with Marfan syndrome lead to an increase in transforming growth factor β (TGF-β) activation in connective tissues resulting in pathogenic changes including aortic dilatation and dissection. Since FBN1 binds latent TGF-β binding proteins (LTBPs), the major reservoir of TGF-β in the extracellular matrix (ECM), we investigated the structural basis for the FBN1/LTBP1 interaction. We present the structure of a four-domain FBN1 fragment, EGF2-EGF3-Hyb1-cbEGF1 (FBN1(E2cbEGF1)), which reveals a near-linear domain organization...
June 21, 2017: Structure
https://www.readbyqxmd.com/read/28669632/regulation-of-the-equilibrium-between-closed-and-open-conformations-of-annexin-a2-by-n-terminal-phosphorylation-and-s100a4-binding
#12
Péter Ecsédi, Bence Kiss, Gergő Gógl, László Radnai, László Buday, Kitti Koprivanacz, Károly Liliom, Ibolya Leveles, Beáta Vértessy, Norbert Jeszenői, Csaba Hetényi, Gitta Schlosser, Gergely Katona, László Nyitray
Annexin A2 (ANXA2) has a versatile role in membrane-associated functions including membrane aggregation, endo- and exocytosis, and it is regulated by post-translational modifications and protein-protein interactions through the unstructured N-terminal domain (NTD). Our sequence analysis revealed a short motif responsible for clamping the NTD to the C-terminal core domain (CTD). Structural studies indicated that the flexibility of the NTD and CTD are interrelated and oppositely regulated by Tyr24 phosphorylation and Ser26Glu phosphomimicking mutation...
June 21, 2017: Structure
https://www.readbyqxmd.com/read/28669631/structure-and-cooperativity-of-the-cytosolic-domain-of-the-cora-mg-2-channel-from-escherichia-coli
#13
Michael Lerche, Hena Sandhu, Lukas Flöckner, Martin Högbom, Mikaela Rapp
Structures of the Mg(2+) bound (closed) and apo (open) states of CorA suggests that channel gating is accomplished by rigid-body motions between symmetric and asymmetric assemblies of the cytosolic portions of the five subunits in response to ligand (Mg(2+)) binding/unbinding at interfacial sites. Here, we structurally and biochemically characterize the isolated cytosolic domain from Escherichia coli CorA. The data reveal an Mg(2+)-ligand binding site located in a novel position between each of the five subunits and two Mg(2+) ions trapped inside the pore...
June 19, 2017: Structure
https://www.readbyqxmd.com/read/28669630/crystal-structure-of-the-clock-transactivation-domain-exon19-in-complex-with-a-repressor
#14
Zhiqiang Hou, Lijing Su, Jimin Pei, Nick V Grishin, Hong Zhang
In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC...
June 16, 2017: Structure
https://www.readbyqxmd.com/read/28683276/escorting-client-proteins-to-the-hsp90-molecular-chaperone
#15
Patrik Eickhoff, Alessandro Costa
The co-chaperone complex R2TP assists Hsp90 in the folding and maturation of client proteins such as phosphatidylinositol-3-kinase-like kinases. In this issue of Structure, Rivera-Calzada, Pal et al. (2017) describe the architecture and catalytic properties of R2TP, providing new insights into the interplay between Hsp90 and its co-chaperones.
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28683275/capturing-the-dynamics-of-a-spring-loaded-protein
#16
Joshua A Mitchell, Megan L O'Mara
Skp and other holdase chaperones bind unfolded bacterial outer membrane proteins, preventing premature folding until they insert into the membrane. In this issue of Structure, Holdbrook et al. (2017) use a combination of NMR, SAXS, ensemble optimization, and MD simulations to show that the Skp chaperone samples a much wider range of conformations than suggested by its structure alone.
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28648612/a-spring-loaded-mechanism-governs-the-clamp-like-dynamics-of-the-skp-chaperone
#17
Daniel A Holdbrook, Björn M Burmann, Roland G Huber, Maxim V Petoukhov, Dmitri I Svergun, Sebastian Hiller, Peter J Bond
The trimeric periplasmic holdase chaperone Skp binds and stabilizes unfolded outer membrane proteins (OMPs) as part of bacterial OMP biogenesis. Skp binds client proteins in its central cavity, thereby reducing its backbone dynamics, but the molecular mechanisms that govern Skp dynamics and adaptation to differently sized clients remains unknown. Here, we employ a combination of microsecond timescale molecular dynamics simulation, small-angle X-ray scattering, and nuclear magnetic resonance spectroscopy to reveal that Skp is remarkably flexible, and features a molecular spring-loaded mechanism in its "tentacle" arms that enables switching between two distinct conformations on sub-millisecond timescales...
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28648611/molecular-switches-of-allosteric-modulation-of-the-metabotropic-glutamate-2-receptor
#18
Laura Pérez-Benito, Maarten L J Doornbos, Arnau Cordomí, Luc Peeters, Hilde Lavreysen, Leonardo Pardo, Gary Tresadern
Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator...
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28648610/glycan-activation-of-a-sheddase-electrostatic-recognition-between-heparin-and-prommp-7
#19
Yan G Fulcher, Stephen H Prior, Sayaka Masuko, Lingyun Li, Dennis Pu, Fuming Zhang, Robert J Linhardt, Steven R Van Doren
Heparan sulfate proteoglycans activate the matrix metalloproteinase-7 zymogen (proMMP-7) and recruit it in order to shed proteins from cell surfaces. This occurs in uterine and mammary epithelia, bacterial killing, lung healing, and tumor cell signaling. Basic tracks on proMMP-7 recognize polyanionic heparin, according to nuclear magnetic resonance and mutations disruptive of maturation. Contacts and proximity measurements guided docking of a heparin octasaccharide to proMMP-7. The reducing end fits into a basic pocket in the pro-domain while the chain continues toward the catalytic domain...
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28648609/critical-role-of-water-molecules-in-proton-translocation-by-the-membrane-bound-transhydrogenase
#20
Pius S Padayatti, Josephine H Leung, Paween Mahinthichaichan, Emad Tajkhorshid, Andrii Ishchenko, Vadim Cherezov, S Michael Soltis, J Baz Jackson, C David Stout, Robert B Gennis, Qinghai Zhang
The nicotinamide nucleotide transhydrogenase (TH) is an integral membrane enzyme that uses the proton-motive force to drive hydride transfer from NADH to NADP(+) in bacteria and eukaryotes. Here we solved a 2.2-Å crystal structure of the TH transmembrane domain (Thermus thermophilus) at pH 6.5. This structure exhibits conformational changes of helix positions from a previous structure solved at pH 8.5, and reveals internal water molecules interacting with residues implicated in proton translocation. Together with molecular dynamics simulations, we show that transient water flows across a narrow pore and a hydrophobic "dry" region in the middle of the membrane channel, with key residues His42(α2) (chain A) being protonated and Thr214(β) (chain B) displaying a conformational change, respectively, to gate the channel access to both cytoplasmic and periplasmic chambers...
July 5, 2017: Structure
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