scholarly journals Structure-based dynamic analysis of the glycine cleavage system suggests key residues for control of a key reaction step

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Han Zhang ◽  
Yuchen Li ◽  
Jinglei Nie ◽  
Jie Ren ◽  
An-Ping Zeng
Keyword(s):  
Dynamic Analysis ◽  
Glycine Cleavage System ◽  
Detailed Structure ◽  
Release Process ◽  
C1 Metabolism ◽  
Molecular Shuttles ◽  
Glycine Cleavage ◽  
Dynamics Simulations ◽  
Molecular Shuttle ◽  
Key Residues

AbstractMolecular shuttles play decisive roles in many multi-enzyme systems such as the glycine cleavage system (GCS) for one-carbon (C1) metabolism. In GCS, a lipoate swinging arm containing an aminomethyl moiety is attached to protein H and serves as a molecular shuttle among different proteins. Protection of the aminomethyl moiety in a cavity of protein H and its release induced by protein T are key processes but barely understood. Here, we present a detailed structure-based dynamic analysis of the induced release of the lipoate arm of protein H. Based on molecular dynamics simulations of interactions between proteins H and T, four major steps of the release process showing significantly different energy barriers and time scales can be distinguished. Mutations of a key residue, Ser-67 in protein H, led to a bidirectional tuning of the release process. This work opens ways to target C1 metabolism in biomedicine and the utilization of formate and CO2 for biosynthesis.

scholarly journals Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

2012 ◽  
Vol 8 ◽  
pp. 1858-1866 ◽  
Author(s):  
Julia Meier ◽  
Kristin Kassler ◽  
Heinrich Sticht ◽  
Jutta Eichler
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Conformational Stability ◽  
Cellular Receptor ◽  
Binding Assays ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Hiv 1

Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability through cyclization, as evidenced by binding assays, as well as through molecular-dynamics simulations of peptide–gp120 complexes. The specificity of the peptide–gp120 interaction was demonstrated by using peptide variants, in which key residues for the interaction with gp120 were replaced by alanine or D-amino acids.

scholarly journals Ion-water coupling controls class A GPCR signal transduction pathways

2020 ◽  
Author(s):  
Neil J. Thomson ◽  
Owen N. Vickery ◽  
Callum M. Ives ◽  
Ulrich Zachariae
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Signal Transmission ◽  
Water Molecules ◽  
Long Distance ◽  
Protein Binding Region ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Extracellular Sodium ◽  
Communication Pathway

G-protein-coupled receptors (GPCRs) transmit signals across the cell membrane, forming the largest family of membrane proteins in humans. Most GPCRs activate through an evolutionarily conserved mechanism, which involves reorientation of helices and key residues, rearrangement of a hydrogen bonding network mediated by water molecules, and the expulsion of a sodium ion from a protonatable binding site. However, how these components interplay to engage the signal effector binding site remains elusive. Here, we applied information theory to molecular dynamics simulations of pharmaceutically important GPCRs to trace concerted conformational variations across the receptors. We discovered a conserved communication pathway that includes protein residues and cofactors and enables the exchange of information between the extracellular sodium binding site and the intracellular G-protein binding region, coupling the most highly conserved protonatable residues at long distance. Reorientation of internal water molecules was found to be essential for signal transmission along this pathway. By inhibiting protonation, sodium decoupled this connectivity, identifying the ion as a master switch that determines the receptors’ ability to move towards active conformations.

scholarly journals Genomic Insights Into the Lifestyles of Thaumarchaeota Inside Sponges

2021 ◽  
Vol 11 ◽  
Author(s):  
Markus Haber ◽  
Ilia Burgsdorf ◽  
Kim M. Handley ◽  
Maxim Rubin-Blum ◽  
Laura Steindler
Keyword(s):  
The Novel ◽  
Glycine Cleavage System ◽  
Free Living ◽  
High Affinity ◽  
Branched Chain Amino Acid ◽  
Glycine Cleavage ◽  
Microbial Symbionts ◽  
Host Sponge ◽  
Branched Chain ◽  
Sponge Symbionts

Sponges are among the oldest metazoans and their success is partly due to their abundant and diverse microbial symbionts. They are one of the few animals that have Thaumarchaeota symbionts. Here we compare genomes of 11 Thaumarchaeota sponge symbionts, including three new genomes, to free-living ones. Like their free-living counterparts, sponge-associated Thaumarchaeota can oxidize ammonia, fix carbon, and produce several vitamins. Adaptions to life inside the sponge host include enrichment in transposases, toxin-antitoxin systems and restriction modifications systems, enrichments previously reported also from bacterial sponge symbionts. Most thaumarchaeal sponge symbionts lost the ability to synthesize rhamnose, which likely alters their cell surface and allows them to evade digestion by the host. All but one archaeal sponge symbiont encoded a high-affinity, branched-chain amino acid transporter system that was absent from the analyzed free-living thaumarchaeota suggesting a mixotrophic lifestyle for the sponge symbionts. Most of the other unique features found in sponge-associated Thaumarchaeota, were limited to only a few specific symbionts. These features included the presence of exopolyphosphatases and a glycine cleavage system found in the novel genomes. Thaumarchaeota have thus likely highly specific interactions with their sponge host, which is supported by the limited number of host sponge species to which each of these symbionts is restricted.

scholarly journals Inhibition of glycine cleavage system by pyridoxine 5′‐phosphate causes synthetic lethality in glyA yggS and serA yggS in Escherichia coli

2019 ◽  
Vol 113 (1) ◽  
pp. 270-284 ◽  
Author(s):  
Tomokazu Ito ◽  
Ran Hori ◽  
Hisashi Hemmi ◽  
Diana M. Downs ◽  
Tohru Yoshimura
Keyword(s):  
Escherichia Coli ◽  
Synthetic Lethality ◽  
Glycine Cleavage System ◽  
Glycine Cleavage

scholarly journals Molecular insights into the interaction of hemorphin and its targets

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amanat Ali ◽  
Bincy Baby ◽  
Soja Saghar Soman ◽  
Ranjit Vijayan
Keyword(s):  
Binding Affinity ◽  
Therapeutic Potential ◽  
Memory Loss ◽  
Interaction Mechanism ◽  
Stable Form ◽  
Endogenous Opioid ◽  
Memory Enhancement ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Potent Therapeutic Agent

Abstract Hemorphins are atypical endogenous opioid peptides produced by the cleavage of hemoglobin beta chain. Several studies have reported the therapeutic potential of hemorphin in memory enhancement, blood regulation, and analgesia. However, the mode of interaction of hemorphin with its target remains largely elusive. The decapeptide LVV-hemorphin-7 is the most stable form of hemorphin. It binds with high affinity to mu-opioid receptors (MOR), angiotensin-converting enzyme (ACE) and insulin-regulated aminopeptidase (IRAP). In this study, computational methods were used extensively to elucidate the most likely binding pose of mammalian LVV-hemorphin-7 with the aforementioned proteins and to calculate the binding affinity. Additionally, alignment of mammalian hemorphin sequences showed that the hemorphin sequence of the camel harbors a variation – a Q > R substitution at position 8. This study also investigated the binding affinity and the interaction mechanism of camel LVV-hemorphin-7 with these proteins. To gain a better understanding of the dynamics of the molecular interactions between the selected targets and hemorphin peptides, 100 ns molecular dynamics simulations of the best-ranked poses were performed. Simulations highlighted major interactions between the peptides and key residues in the binding site of the proteins. Interestingly, camel hemorphin had a higher binding affinity and showed more interactions with all three proteins when compared to the canonical mammalian LVV-hemorphin-7. Thus, camel LVV-hemorphin-7 could be explored as a potent therapeutic agent for memory loss, hypertension, and analgesia.

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