scholarly journals GAI MoRFs Regulate Cleft and Channel Binding Pathways for Gibberellin in GID1A

2020 ◽  
Author(s):  
John Patterson ◽  
Charles C. David ◽  
Marion Wood ◽  
Xiaolin Sun ◽  
Donald J. Jacobs ◽  
...  
Keyword(s):  
Computational Study ◽  
Binding Pocket ◽  
Receptor Complex ◽  
Transcriptional Repressors ◽  
Contact Residues ◽  
Presence And Absence ◽  
Molecular Recognition Features ◽  
Signalling Cascade ◽  
Rapid Binding ◽  
Rectification Process

The hormone gibberellin (GA) promotes arabidopsis growth by enhancing binding between GA Insensitive DELLA transcriptional repressors and GA Insensitive Dwarf 1 (GID1) receptors to regulate DELLA degradation. The binding mechanism for GA was elucidated by employing a computational study of dissociations of the N-terminus of the DELLA family member GAI (GA Insensitive transcriptional repressor) from the GID1A receptor in the presence and absence of bound GA, and of GA from GID1A in the presence and absence of GAI. The tRAMD method was employed to deduce egression pathways for a diverse set of GA molecules (GA (x) ). Two pathways in the form of a newly identified cleft and a previously identified channel are prevalent. The cleft pathway is open in the absence of GAI. Upon GAI binding, the cleft route is blocked, resulting in a slower process for GA (x) to exit and enter the binding pocket through the channel. Several binding pocket residues are identified as gate-keepers to the channel. Molecular recognition features (MoRFs) found in the disordered signaling protein GAI affect GA (x) binding and GID1A dynamics. A three-step synergistic binding cycle is proposed where GAI MoRFs regulate the process. Rapid binding takes place through the cleft where little to no distinctions are made between major and less active forms of GA (x) . After GAI is bound to the GA (x) [[EQUATION]] GID1A complex, the channel supports a rectification process that increases the retention of major active forms of GA within the binding pocket. Both the cleft and channel contact residues to GA (x) are markedly conserved in a GID1 phylogeny, suggesting this binding process in the GID1 [[EQUATION]] DELLA GA-receptor complex represents a general paradigm for GA binding. Non-specific GA binding assists binding of GAI, which then helps to select the major active forms of the hormone and induce a downstream signalling cascade in response to bioactive GA.

scholarly journals Interaction of Azospirillum lipoferumwith Wheat Germ Agglutinin Stimulates Nitrogen Fixation

1999 ◽  
Vol 181 (13) ◽  
pp. 3949-3955 ◽  
Author(s):  
Eva Karpati ◽  
Peter Kiss ◽  
Tamas Ponyi ◽  
Istvan Fendrik ◽  
Miklos de Zamaroczy ◽  
...  
Keyword(s):  
Nitrogen Fixation ◽  
Gene Cluster ◽  
Binding Sites ◽  
Wheat Germ Agglutinin ◽  
Wheat Germ ◽  
Side Chains ◽  
Receptor Complex ◽  
Sugar Binding ◽  
Signalling Cascade

ABSTRACT In vitro, the nitrogen fixation capability of A. lipoferum is efficiently increased in the presence of wheat germ agglutinin (WGA). A putative WGA-binding receptor, a 32-kDa protein, was detected in the cell capsule. The stimulatory effect requiredN-acetyl-d-glucosamine dimer (GlcNAcdi) terminated sugar side chains of the receptor and was dependent on the number of GlcNAcdi links involved in receptor-WGA interface. Binding to the primary sugar binding sites on WGA had a larger stimulatory effect than binding to the secondary sites. The WGA-receptor complex generated stimulus led to elevated transcription of the nifH and nifA genes and of the glnBA gene cluster but not of the glnA gene from its own promoter. There may well be a signalling cascade contributing to the regulation of nitrogen fixation.

A Computational Study to Prevent HIV Invasion by Bovine LF in Mucosal-Layer via Blocking of DC-SIGN_GP120 Interaction

2020 ◽  
Vol 17 (5) ◽  
pp. 413-424
Author(s):  
Arundhati Banerjee ◽  
Rakhi Dasgupta ◽  
Sujay Ray
Keyword(s):  
Computational Study ◽  
Sexual Transmission ◽  
Pharmaceutical Research ◽  
Active Role ◽  
Binding Pocket ◽  
Protein Docking ◽  
Bovine Lactoferrin ◽  
Stability Parameters ◽  
Mucosal Layer ◽  
Mucosal Lining

Background: Invasion of HIV in human occurs through DC-SIGN’s interaction via the mucosal lining during sexual transmission. Bovine Lactoferrin (bLF) has been known to hinder this invasion via its interaction with DC-SIGN. Hitherto, protein assays have taken place but molecular-level studies remain unexplored. Methodology: The 3D structures of the three proteins were studied. After protein docking (bLF_DCSIGN and gp120_DC-SIGN), the complexes underwent simulation. Stability parameters and binding patterns with residues were explored. Results and Conclusion: ΔG values, net area for solvent accessibilities and conformational fluctuations in DC-SIGN affirm the binding of bLF with DC-SIGN to be more spontaneous and steadier contrary to that with gp120. Residue participation inferred more interactions to occur from bLF complex with a greater percentage of arginine (which strengthens the interaction) while electrostatic interaction between Lys45 (bLF) and Glu26 (DC-SIGN) strengthened the complex. Arg37 played an active role from DC-SIGN to form the stabilizing charged-neutral H-bond, while Lys63 from bLF formed two more such stabilizing charged-neutral H-bond with DC-SIGN. The prime binding sites in DC-SIGN; Arg37 and Gln34 occupy helices. The binding pockets in DC-SIGN may be blocked by bLF spontaneously, to hinder their interaction with gp120. No ionic-ionic interaction was observed from gp120_DCSIGN complex. 88th residue, which was a predominant residue in the binding pocket was found to experience a conformational shift from coils to sheets after interaction of DC-SIGN with bLF. This would instigate the pharmaceutical research as non-toxic LF would be economic as a remarkable peptide inhibitor opposing HIV.

scholarly journals DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

Blood ◽  
2012 ◽  
Vol 120 (6) ◽  
pp. 1228-1236 ◽  
Author(s):  
Kinga K. Hosszu ◽  
Alisa Valentino ◽  
Uma Vinayagasundaram ◽  
Rama Vinayagasundaram ◽  
M. Gordon Joyce ◽  
...  
Keyword(s):  
Immunofluorescence Microscopy ◽  
Binding Pocket ◽  
Receptor Complex ◽  
Surface Plasmon Resonance Analysis ◽  
Resonance Analysis ◽  
Antigen Capture ◽  
Immature Dendritic Cells ◽  
A Chain ◽  
And Function ◽  
Cell Signaling Pathways

AbstractC1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface—gC1qR and cC1qR—lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca2+ and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca2+-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN–mediated induction of cell-signaling pathways.

scholarly journals Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 913
Author(s):  
Manabu Igarashi ◽  
Takatsugu Hirokawa ◽  
Yoshihiro Takadate ◽  
Ayato Takada
Keyword(s):  
Receptor Binding ◽  
Ebola Virus ◽  
Computational Study ◽  
Binding Pocket ◽  
Crystal Structure Analysis ◽  
Receptor Binding Site ◽  
Structure Based Drug Design ◽  
Niemann Pick ◽  
Dynamics Simulations ◽  
Loop 2

Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. The crystal structure analysis of the cleaved GP (GPcl) of Ebola virus (EBOV) in complex with human NPC1 has demonstrated that NPC1 has two protruding loops (loops 1 and 2), which engage a hydrophobic pocket on the head of EBOV GPcl. However, the molecular interactions between NPC1 and the GPcl of other filoviruses remain unexplored. In the present study, we performed molecular modeling and molecular dynamics simulations of NPC1 complexed with GPcls of two ebolaviruses, EBOV and Sudan virus (SUDV), and one marburgvirus, Ravn virus (RAVV). Similar binding structures were observed in the GPcl–NPC1 complexes of EBOV and SUDV, which differed from that of RAVV. Specifically, in the RAVV GPcl–NPC1 complex, the tip of loop 2 was closer to the pocket edge comprising residues at positions 79–88 of GPcl; the root of loop 1 was predicted to interact with P116 and Q144 of GPcl. Furthermore, in the SUDV GPcl–NPC1 complex, the tip of loop 2 was slightly closer to the residue at position 141 than those in the EBOV and RAVV GPcl–NPC1 complexes. These structural differences may affect the size and/or shape of the receptor-binding pocket of GPcl. Our structural models could provide useful information for improving our understanding the differences in host preference among filoviruses as well as contributing to structure-based drug design.

scholarly journals High-order epistasis in catalytic power of dihydrofolate reductase gives rise to a rugged fitness landscape in the presence of trimethoprim selection

2018 ◽  
Author(s):  
Yusuf Talha Tamer ◽  
Ilona K. Gaszek ◽  
Haleh Abdizadeh ◽  
Tugce Altinusak Batur ◽  
Kimberly Reynolds ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Biochemical Parameters ◽  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Computational Study ◽  
Binding Pocket ◽  
Resistance Mechanisms ◽  
Fitness Landscapes ◽  
High Order ◽  
Catalytic Power

ABSTRACTEvolutionary fitness landscapes of certain antibiotic target enzymes have been comprehensively mapped showing strong high order epistasis between mutations, but understanding these effects at the biochemical and molecular levels remained open. Here, we carried out an extensive experimental and computational study to quantitatively understand the evolutionary dynamics of Escherichia coli dihydrofolate reductase (DHFR) enzyme in the presence of trimethoprim induced selection. Biochemical and structural characterization of resistance-conferring mutations targeting a total of ten residues spanning the substrate binding pocket of DHFR revealed distinct resistance mechanisms. Next, we experimentally measured biochemical parameters (Km, Ki, and kcat) for a mutant library carrying all possible combinations of six resistance-conferring DHFR mutations and quantified epistatic interactions between them. We found that the epistasis between DHFR mutations is high-order for catalytic power of DHFR (kcat and Km), but less prevalent for trimethoprim affinity (Ki). Taken together our data provide a concrete illustration of how epistatic coupling at the level of biochemical parameters can give rise to complex fitness landscapes, and suggest new strategies for developing mutant specific inhibitors.

scholarly journals A computational approach to evaluate the combined effect of SARS-CoV-2 RBD mutations and ACE2 receptor genetic variants on infectivity: The COVID-19 host-pathogen nexus

2020 ◽  
Author(s):  
Dana Ashoor ◽  
Noureddine Ben Khalaf ◽  
Maryam Marzouq ◽  
Hamdi Jarjanazi ◽  
Sadok Chelif ◽  
...  
Keyword(s):  
3D Model ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Computational Approach ◽  
Receptor Complex ◽  
Complex Stability ◽  
Virus Receptor ◽  
Contact Residues ◽  
The Stability ◽  
Virus Spreading

Abstract: SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (∆∆G) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

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