Novel structural features of autoantibodies in murine lupus: A possible superantigen binding site?

1994 ◽  
Vol 72 (6) ◽  
pp. 513-520 ◽  
Author(s):  
D. JESKE ZACK ◽  
A. L. WONG ◽  
R. H. WEISBART
Keyword(s):  
Binding Site ◽  
Structural Features ◽  
Murine Lupus

scholarly journals Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4904
Author(s):  
Gaia Pasqualetto ◽  
Martin Schepelmann ◽  
Carmine Varricchio ◽  
Elisa Pileggi ◽  
Caroline Khogali ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Small Molecules ◽  
Binding Site ◽  
Photoreceptor Cells ◽  
Structural Features ◽  
Outer Cell ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
In Silico Studies ◽  
Leber’S Congenital Amaurosis

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.

Symmetric Structural Features and Binding Site of the Primary Electron Donor in the Reaction Center of Chlorobium

Biochemistry ◽  
1995 ◽  
Vol 34 (35) ◽  
pp. 11099-11105 ◽  
Author(s):  
Ute Feiler ◽  
Delphine Albouy ◽  
Bruno Robert ◽  
Tony A. Mattioli
Keyword(s):  
Binding Site ◽  
Reaction Center ◽  
Electron Donor ◽  
Structural Features ◽  
Primary Electron ◽  
Primary Electron Donor

scholarly journals Single particle cryo-EM structure of the outer hair cell motor protein prestin

2021 ◽  
Author(s):  
Carmen BUtan ◽  
Qiang Song ◽  
Jun-ping Bai ◽  
Winston Tan ◽  
Dhasakumar S Navaratnam ◽  
...  
Keyword(s):  
Hair Cell ◽  
Binding Site ◽  
Outer Hair Cell ◽  
Three Dimensional ◽  
Structural Features ◽  
Meriones Unguiculatus ◽  
Dimensional Structure ◽  
Transmembrane Segments ◽  
Anion Transporter ◽  
Mechanistic Basis

The mammalian outer hair cell (OHC) protein prestin (Slc26a5), a member of the solute carrier 26 (Slc26) family of membrane proteins, differs from other members of the family owing to its unique piezoelectric-like property that drives OHC electromotility. Prestin is required by OHCs for cochlear amplification, a process that enhances mammalian hearing. Despite substantial biophysical characterization, the mechanistic basis for the prestins electro-mechanical behavior is not fully understood. To gain insight into such behavior, we have used cryo-electron microscopy at subnanometer resolution (overall resolution of 4.0 Å) to investigate the three-dimensional structure of prestin from gerbil (Meriones unguiculatus). Our studies show that prestin dimerizes with a 3D architecture strikingly similar to the dimeric conformation observed in the Slc26a9 anion transporter in an inside open/intermediate state, which we infer, based on patch clamp recordings, to reflect the contracted state of prestin. The structure shows two well separated transmembrane (TM) subunits and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains forming a swapped dimer. The dimerization interface is defined by interactions between the domain-swapped STAS dimer and the transmembrane domains of the opposing half unit, further strengthened by an antiparallel beta strand at its N terminus. The structure also shows that each one of its two transmembrane subunits consists of 14 transmembrane segments organized in two inverted 7-segment repeats with a topology that was first observed in the structure of the bacterial symporter UraA (Lu F, et al., Nature 472, 2011). Finally, the solved anion binding site structural features of prestin are quite similar to that of SLC26a9 and other family members. Despite this similarity, we find that SLC26a9 lacks the characteristic displacement currents (or NonLinear Capacitance(NLC)) found with prestin, and we show that mutation of prestins Cl- binding site removes salicylate competition with anions in the face of normal NLC, thus refuting the yet accepted extrinsic voltage sensor hypothesis and any associated transport-like requirements for voltage-driven electromotility.

scholarly journals Self-association configures the NAD+-binding site of plant NLR TIR domains

2021 ◽  
Author(s):  
Hayden Burdett ◽  
Xiahao Hu ◽  
Maxwell X Rank ◽  
Natsumi Maruta ◽  
Bostjan Kobe
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Active Site ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Structural Features ◽  
Active Conformation ◽  
Effector Triggered Immunity ◽  
Self Association ◽  
Tir Domains

TIR domains are signalling domains present in plant nucleotide-binding leucine-rich repeat receptors (NLRs), with key roles in plant innate immunity. They are required for the induction of a hypersensitive response (HR) in effector-triggered immunity, but the mechanism by which this occurs is not yet fully understood. It has been recently shown that the TIR domains from several plant NLRs possess NADase activity. The oligomeric structure of TIR-containing NLRs ROQ1 and RPP1 reveals how the TIR domains arrange into an active conformation, but low resolution around the NAD+ binding sites leaves questions unanswered about the molecular mechanisms linking self-association and NADase activity. In this study, a number of crystal structures of the TIR domain from the grapevine NLR RUN1 reveal how self-association and enzymatic activity may be linked. Structural features previously proposed to play roles involve the ″AE interface″ (mediated by helices A and E), the ″BB-loop″ (connecting β-strand B and helix B in the structure), and the ″BE interface″ (mediated by the BB-loop from one TIR and the ″DE surface″ of another). We demonstrate that self-association through the AE interface induces conformational changes in the NAD+-binding site, shifting the BB-loop away from the catalytic site and allowing NAD+ to access the active site. We propose that an intact ″DE surface″ is necessary for production of the signalling product (variant cyclic ADPR), as it constitutes part of the active site. Addition of NAD+ or NADP+ is not sufficient to induce self-association, suggesting that NAD+ binding occurs after TIR self-association. Our study identifies a mechanistic link between TIR self-association and NADase activity.

scholarly journals Characterization of cathepsin S exosites that govern its elastolytic activity

2020 ◽  
Vol 477 (1) ◽  
pp. 227-242 ◽  
Author(s):  
Pierre-Marie Andrault ◽  
Preety Panwar ◽  
Dieter Brömme
Keyword(s):  
Binding Site ◽  
Structural Features ◽  
Docking Studies ◽  
Structural Examination ◽  
Structural Localization ◽  
Elastin Degradation ◽  
Basement Membrane Component ◽  
Elastolytic Activity ◽  
The Right

We have previously determined that the elastolytic activities of cathepsins (Cat) K and V require two exosites sharing the same structural localization on both enzymes. The structural features involved in the elastolytic activity of CatS have not yet been identified. We first mutated the analogous CatK and V putative exosites of CatS into the elastolytically inactive CatL counterparts. The modification of the exosite 1 did not affect the elastase activity of CatS whilst mutation of the Y118 of exosite 2 decreased the cleavage of elastin by ∼70% without affecting the degradation of other macromolecular substrates (gelatin, thyroglobulin). T06, an ectosteric inhibitor that disrupt the elastolytic activity of CatK, blocked ∼80% of the elastolytic activity of CatS without blocking the cleavage of gelatin and thyroglobulin. Docking studies showed that T06 preferentially interacts with a binding site located on the Right domain of the enzyme, outside of the active site. The structural examination of this binding site showed that the loop spanning the L174N175G176K177 residues of CatS is considerably different from that of CatL. Mutation of this loop into the CatL-like equivalent decreased elastin degradation by ∼70% and adding the Y118 mutation brought down the loss of elastolysis to ∼80%. In addition, the Y118 mutation selectively reduced the cleavage of the basement membrane component laminin by ∼50%. In summary, our data show that the degradation of elastin by CatS requires two exosites where one of them is distinct from those of CatK and V whilst the cleavage of laminin requires only one exosite.

Glycogen phosphorylase revisited: extending the resolution of the R- and T-state structures of the free enzyme and in complex with allosteric activators

2021 ◽  
Vol 77 (9) ◽  
pp. 303-311
Author(s):  
Demetres D. Leonidas ◽  
Spyros E. Zographos ◽  
Katerina E. Tsitsanou ◽  
Vassiliki T. Skamnaki ◽  
George Stravodimos ◽  
...  
Keyword(s):  
Drug Design ◽  
Binding Site ◽  
Crystal Structures ◽  
Glycogen Phosphorylase ◽  
Structural Features ◽  
Terminal Segment ◽  
Structure Based Drug Design ◽  
Allosteric Transition ◽  
Α Helix ◽  
T State

The crystal structures of free T-state and R-state glycogen phosphorylase (GP) and of R-state GP in complex with the allosteric activators IMP and AMP are reported at improved resolution. GP is a validated pharmaceutical target for the development of antihyperglycaemic agents, and the reported structures may have a significant impact on structure-based drug-design efforts. Comparisons with previously reported structures at lower resolution reveal the detailed conformation of important structural features in the allosteric transition of GP from the T-state to the R-state. The conformation of the N-terminal segment (residues 7–17), the position of which was not located in previous T-state structures, was revealed to form an α-helix (now termed α0). The conformation of this segment (which contains Ser14, phosphorylation of which leads to the activation of GP) is significantly different between the T-state and the R-state, pointing in opposite directions. In the T-state it is packed between helices α4 and α16 (residues 104–115 and 497–508, respectively), while in the R-state it is packed against helix α1 (residues 22′–38′) and towards the loop connecting helices α4′ and α5′ of the neighbouring subunit. The allosteric binding site where AMP and IMP bind is formed by the ordering of a loop (residues 313–326) which is disordered in the free structure, and adopts a conformation dictated mainly by the type of nucleotide that binds at this site.

DNA shape complements sequence-based representations of transcription factor binding sites

2019 ◽  
Author(s):  
Peter DeFord ◽  
James Taylor
Keyword(s):  
Transcription Factor ◽  
Binding Site ◽  
Binding Sites ◽  
Structural Features ◽  
Structural Motif ◽  
Dna Motif ◽  
Binding Site Identification ◽  
Encoding Strategies ◽  
Encoding Strategy ◽  
Site Identification

AbstractThe position weight matrix (PWM) has long been a useful tool for describing variation in the composition of regions of DNA such as transcription factor (TF) binding sites. It is difficult, however, to relate the sequence-based representation of a DNA motif to the biological features of the interaction of a TF with its binding site. Here we present an alternative strategy for representing DNA motifs – called Structural Motif (StruM) – that can easily represent different sets of structural features. Structural features are inferred from dinucleotide properties listed in the Dinucleotide Property Database. StruMs are able to specifically model TF binding sites, using an encoding strategy that is distinct from sequence-based models. This difference in encoding strategies makes StruMs complementary to sequence-based methods of TF binding site identification.

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