Three-Dimensional Structure of the Gap Junction Connexon and Intercellular Channel

1997 ◽  
Vol 3 (S2) ◽  
pp. 227-228
Author(s):  
Guy Perkins ◽  
Dan Goodenough ◽  
Gina Sosinsky
Keyword(s):  
Small Molecules ◽  
Gap Junction ◽  
Three Dimensional ◽  
Surface Topology ◽  
Dimensional Structure ◽  
Cell Contact ◽  
Membrane Channels ◽  
Membrane Channel ◽  
Contact Areas ◽  
Intercellular Channel

Gap junctions are specialized cell-cell contact areas by which cells communication with each other. Within these contact areas are tens to thousands of membrane channels. A gap junction membrane channel (also referred to as an intercellular channel) is unique among membrane channels in that it is composed of two oligomers with each of two adjacent tissue cells contributing one oligomer (called a connexon or hemichannel). The pore of the intercellular channel controls the passage of small molecules and ions from one cell to another.We are interested in how the structure and surface topology of the gap junction connexon at its extracellular surface influences the docking and formation of an intercellular communicating channel. It has been demonstrated that connexons made from some connexins will dock and form functional channels with some but not all connexons made from other isoforms. This selectivity is surprising considering that the primary sequences of the docking domains are highly conserved.

Using 3D printed physical models to monitor knowledge integration in biochemistry

2018 ◽  
Vol 19 (4) ◽  
pp. 1199-1215 ◽  
Author(s):  
Melissa A. Babilonia-Rosa ◽  
H. Kenny Kuo ◽  
Maria T. Oliver-Hoyo
Keyword(s):  
Small Molecules ◽  
Knowledge Integration ◽  
Noncovalent Interactions ◽  
Three Dimensional ◽  
Student Understanding ◽  
Physical Models ◽  
Dimensional Structure ◽  
Instructional Resources ◽  
3D Printed ◽  
Different Sources

Noncovalent interactions determine the three-dimensional structure of macromolecules and the binding interactions between molecules. Students struggle to understand noncovalent interactions and how they relate to structure–function relationships. Additionally, students’ difficulties translating from two-dimensional representations to three-dimensional representations add another layer of complexity found in macromolecules. Therefore, we developed instructional resources that use 3D physical models to target student understanding of noncovalent interactions of small molecules and macromolecules. To this effect, we monitored indicators of knowledge integration as evidenced in student-generated drawings. Analysis of the drawings revealed that students were able to incorporate relevant conceptual features into their drawings from different sources as well as present their understanding from different perspectives.

scholarly journals Susceptibility of protein therapeutics to spontaneous chemical modifications by oxidation, cyclization, and elimination reactions

Amino Acids ◽  
2019 ◽  
Vol 51 (10-12) ◽  
pp. 1409-1431 ◽  
Author(s):  
Luigi Grassi ◽  
Chiara Cabrele
Keyword(s):  
Small Molecules ◽  
Three Dimensional ◽  
Drug Market ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Chemical Modifications ◽  
Small Molecule Drugs ◽  
And Function ◽  
The Impact

Abstract Peptides and proteins are preponderantly emerging in the drug market, as shown by the increasing number of biopharmaceutics already approved or under development. Biomolecules like recombinant monoclonal antibodies have high therapeutic efficacy and offer a valuable alternative to small-molecule drugs. However, due to their complex three-dimensional structure and the presence of many functional groups, the occurrence of spontaneous conformational and chemical changes is much higher for peptides and proteins than for small molecules. The characterization of biotherapeutics with modern and sophisticated analytical methods has revealed the presence of contaminants that mainly arise from oxidation- and elimination-prone amino-acid side chains. This review focuses on protein chemical modifications that may take place during storage due to (1) oxidation (methionine, cysteine, histidine, tyrosine, tryptophan, and phenylalanine), (2) intra- and inter-residue cyclization (aspartic and glutamic acid, asparagine, glutamine, N-terminal dipeptidyl motifs), and (3) β-elimination (serine, threonine, cysteine, cystine) reactions. It also includes some examples of the impact of such modifications on protein structure and function.

scholarly journals Three-Dimensional Structure of the Intercalated Disc Reveals Plicate Domain and Gap Junction Remodeling in Heart Failure

2015 ◽  
Vol 108 (3) ◽  
pp. 498-507 ◽  
Author(s):  
Christian Pinali ◽  
Hayley J. Bennett ◽  
J. Bernard Davenport ◽  
Jessica L. Caldwell ◽  
Tobias Starborg ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gap Junction ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Intercalated Disc ◽  
Three Dimensional Structure

scholarly journals Three-Dimensional Structure of the Gap Junction Connexon

1997 ◽  
Vol 72 (2) ◽  
pp. 533-544 ◽  
Author(s):  
Guy Perkins ◽  
Dan Goodenough ◽  
Gina Sosinsky
Keyword(s):  
Gap Junction ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Three Dimensional Structure

scholarly journals Three-Dimensional Structure of Innexin GAP Junction Channels Studied by Electron Crystallography

2016 ◽  
Vol 110 (3) ◽  
pp. 352a-353a
Author(s):  
Atsunori Oshima ◽  
Tomohiro Matsuzawa ◽  
Kazuyoshi Murata ◽  
Kazutoshi Tani ◽  
Yoshinori Fujiyoshi
Keyword(s):  
Gap Junction ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Electron Crystallography ◽  
Three Dimensional Structure ◽  
Gap Junction Channels

scholarly journals 2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

2020 ◽  
Author(s):  
Andrew T. Chang ◽  
Lu Chen ◽  
Luo Song ◽  
Shuxing Zhang ◽  
Edward P. Nikonowicz
Keyword(s):  
Small Molecules ◽  
Dipolar Coupling ◽  
Residual Dipolar Coupling ◽  
Three Dimensional ◽  
Coupling Constants ◽  
Dimensional Structure ◽  
Flanking Sequence ◽  
Base Pairs ◽  
Virtual Screen ◽  
Rna Hairpin

AbstractRNA helices are often punctuated with non-Watson-Crick features that can be the target of chemical compounds, but progress towards identifying small molecules specific for non-canonical elements has been slow. We have used a tandem UU:GA mismatch motif (5’-UG-3’:5’-AU-3’) embedded within the helix of an RNA hairpin as a model to identify compounds that bind the motif specifically. The three-dimensional structure of the RNA hairpin and its interaction with a small molecule compound identified through a virtual screen are presented. The G-A of the mismatch forms a sheared pair upon which the U-U base pair stacks. The hydrogen bond configuration of the U-U pair involves the O2 of the U adjacent to the G and the O4 of the U adjacent to the A. The G-A and U-U pairs are flanked by A-U and G-C base pairs, respectively, and the mismatch exhibits greater stability than when the motif is within the context of other flanking base pairs or when the 5’-3’ orientation of the G-A and U-U is swapped. Residual dipolar coupling constants were used to generate an ensemble of structures against which a virtual screen of 64,480 small molecules was performed to identify candidate compounds that the motif specifically binds. The tandem mismatch was found to be specific for one compound, 2-amino-1,3-benzothiazole-6-carboxamide, which binds with moderate affinity but extends the motif to include the flanking A-U and G-C base pairs. The finding that affinity for the UU:GA mismatch is flanking sequence dependent emphasizes the importance of motif context and potentially increases the number of small non-canonical features within RNA that can be specifically targeted by small molecules.

scholarly journals Cryo-electron Microscopy and Exploratory Antisense Targeting of the 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome

2020 ◽  
Author(s):  
Kaiming Zhang ◽  
Ivan N. Zheludev ◽  
Rachel J. Hagey ◽  
Marie Teng-Pei Wu ◽  
Raphael Haslecker ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Small Molecules ◽  
Tertiary Structure ◽  
Three Dimensional ◽  
Locked Nucleic Acid ◽  
Dimensional Structure ◽  
Potential Candidate ◽  
Cryo Electron Microscopy ◽  
Rna Genome ◽  
Cellular Replication

AbstractDrug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome1, 2. The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides3–6. To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve7 pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 Å, presents a topologically complex fold in which the 5′ end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules.

scholarly journals Human Bocavirus Capsid Structure: Insights into the Structural Repertoire of the Parvoviridae

2010 ◽  
Vol 84 (12) ◽  
pp. 5880-5889 ◽  
Author(s):  
Brittney L. Gurda ◽  
Kristin N. Parent ◽  
Heather Bladek ◽  
Robert S. Sinkovits ◽  
Michael A. DiMattia ◽  
...  
Keyword(s):  
Parvovirus B19 ◽  
Three Dimensional ◽  
Surface Topology ◽  
Dimensional Structure ◽  
Human Bocavirus ◽  
Dna Viruses ◽  
Variable Surface ◽  
Antigenic Properties ◽  
Α Helix ◽  
Tract Infections

ABSTRACT Human bocavirus (HBoV) was recently discovered and classified in the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae) on the basis of genomic similarity to bovine parvovirus and canine minute virus. HBoV has been implicated in respiratory tract infections and gastroenteric disease in children worldwide, yet despite numerous epidemiological reports, there has been limited biochemical and molecular characterization of the virus. Reported here is the three-dimensional structure of recombinant HBoV capsids, assembled from viral protein 2 (VP2), at 7.9-Å resolution as determined by cryo-electron microscopy and image reconstruction. A pseudo-atomic model of HBoV VP2 was derived from sequence alignment analysis and knowledge of the crystal structure of human parvovirus B19 (genus Erythrovirus). Comparison of the HBoV capsid structure to that of parvoviruses from five separate genera demonstrates strong conservation of a β-barrel core domain and an α-helix, from which emanate several loops of various lengths and conformations, yielding a unique surface topology that differs from the three already described for this family. The highly conserved core is consistent with observations for other single-stranded DNA viruses, and variable surface loops have been shown to confer the host-specific tropism and the diverse antigenic properties of this family.

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