scholarly journals Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Iga Kucharska ◽  
Elaine Thai ◽  
Ananya Srivastava ◽  
John L Rubinstein ◽  
Régis Pomès ◽  
...  
Keyword(s):  
Plasmodium Species ◽  
Humoral Response ◽  
Circumsporozoite Protein ◽  
Inhibitory Antibody ◽  
Structural Ordering ◽  
X Ray ◽  
X Ray Crystallography ◽  
Antibody Recognition ◽  
Structural Details ◽  
Dynamics Simulations

Plasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 – the leading malaria vaccine against P. falciparum (Pf) – has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.

scholarly journals Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11

2020 ◽  
Author(s):  
Iga Kucharska ◽  
Elaine Thai ◽  
Ananya Srivastava ◽  
John Rubinstein ◽  
Régis Pomès ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Humoral Response ◽  
Circumsporozoite Protein ◽  
Inhibitory Antibody ◽  
Structural Ordering ◽  
X Ray ◽  
X Ray Crystallography ◽  
Antibody Recognition ◽  
Structural Details ◽  
Dynamics Simulations

ABSTRACTPlasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 – the leading malaria vaccine against P. falciparum (Pf) – has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.

scholarly journals Temperature-dependent macromolecular X-ray crystallography

2010 ◽  
Vol 66 (4) ◽  
pp. 437-446 ◽  
Author(s):  
Martin Weik ◽  
Jacques-Philippe Colletier
Keyword(s):  
Radiation Damage ◽  
Routine Data ◽  
Dynamical Behaviour ◽  
Biological Macromolecules ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structural Details ◽  
Induced Changes ◽  
Structural Insights ◽  
Reaction Initiation

X-ray crystallography provides structural details of biological macromolecules. Whereas routine data are collected close to 100 K in order to mitigate radiation damage, more exotic temperature-controlled experiments in a broader temperature range from 15 K to room temperature can provide both dynamical and structural insights. Here, the dynamical behaviour of crystalline macromolecules and their surrounding solvent as a function of cryo-temperature is reviewed. Experimental strategies of kinetic crystallography are discussed that have allowed the generation and trapping of macromolecular intermediate states by combining reaction initiation in the crystalline state with appropriate temperature profiles. A particular focus is on recruiting X-ray-induced changes for reaction initiation, thus unveiling useful aspects of radiation damage, which otherwise has to be minimized in macromolecular crystallography.

scholarly journals Elucidation of Lipid Binding Sites on Lung Surfactant Protein A Using X-ray Crystallography, Mutagenesis, and Molecular Dynamics Simulations

Biochemistry ◽  
2016 ◽  
Vol 55 (26) ◽  
pp. 3692-3701 ◽  
Author(s):  
Boon Chong Goh ◽  
Huixing Wu ◽  
Michael J. Rynkiewicz ◽  
Klaus Schulten ◽  
Barbara A. Seaton ◽  
...  
Keyword(s):  
Binding Sites ◽  
Lung Surfactant ◽  
Protein A ◽  
Surfactant Protein ◽  
Lipid Binding ◽  
Surfactant Protein A ◽  
X Ray ◽  
X Ray Crystallography ◽  
Lung Surfactant Protein ◽  
Dynamics Simulations

scholarly journals Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Iga Kucharska ◽  
Lamia Hossain ◽  
Danton Ivanochko ◽  
Qiren Yang ◽  
John L Rubinstein ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Molecular Basis ◽  
Parasite Infection ◽  
Circumsporozoite Protein ◽  
Structural Basis ◽  
Structural Studies ◽  
Repeat Region ◽  
Antibody Recognition ◽  
Peptide Conformations ◽  
Dynamics Simulations

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

scholarly journals Mixed Chirality α-Helix in a Stapled Bicyclic and a Linear Antimicrobial Peptide Revealed by X-Ray Crystallography

2021 ◽  
Author(s):  
stéphane Baeriswyl ◽  
Hippolyte Personne ◽  
Ivan Di Bonaventura ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
...  
Keyword(s):  
Bioactive Peptides ◽  
Multidrug Resistant ◽  
Isobutyric Acid ◽  
Resistant Bacteria ◽  
X Ray ◽  
X Ray Crystallography ◽  
Left Handed ◽  
Amino Isobutyric Acid ◽  
Α Helix ◽  
Dynamics Simulations

<p>The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality. What happens in between is largely unknown, however α-helices have not been reported with mixed chirality sequences unless a strong non-natural helix inducer such as amino-isobutyric acid was used. Herein we report the discovery of a membrane disruptive amphiphilic antimicrobial undecapeptide containing seven L- and four D-residues forming a stable right-handed α-helix in stapled bicyclic and linear forms. The α-helical fold is evidenced by X-ray crystallography and supported in solution by circular dichroism spectra as well as molecular dynamics simulations. The linear mixed chirality peptide is as active as the L-sequence against multidrug resistant bacteria but shows no hemolysis and full stability against serum proteolysis. Searching for mixed chirality analogs preserving folding might be generally useful to optimize α-helical bioactive peptides. </p>

scholarly journals Mixed Chirality α-Helix in a Stapled Bicyclic and a Linear Antimicrobial Peptide Revealed by X-Ray Crystallography

2021 ◽  
Author(s):  
stéphane Baeriswyl ◽  
Hippolyte Personne ◽  
Ivan Di Bonaventura ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
...  
Keyword(s):  
Bioactive Peptides ◽  
Multidrug Resistant ◽  
Isobutyric Acid ◽  
Resistant Bacteria ◽  
X Ray ◽  
X Ray Crystallography ◽  
Left Handed ◽  
Amino Isobutyric Acid ◽  
Α Helix ◽  
Dynamics Simulations

<p>The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality. What happens in between is largely unknown, however α-helices have not been reported with mixed chirality sequences unless a strong non-natural helix inducer such as amino-isobutyric acid was used. Herein we report the discovery of a membrane disruptive amphiphilic antimicrobial undecapeptide containing seven L- and four D-residues forming a stable right-handed α-helix in stapled bicyclic and linear forms. The α-helical fold is evidenced by X-ray crystallography and supported in solution by circular dichroism spectra as well as molecular dynamics simulations. The linear mixed chirality peptide is as active as the L-sequence against multidrug resistant bacteria but shows no hemolysis and full stability against serum proteolysis. Searching for mixed chirality analogs preserving folding might be generally useful to optimize α-helical bioactive peptides. </p>

scholarly journals A pharmacological master key mechanism that unlocks the selectivity filter gate in K+channels

Science ◽  
2019 ◽  
Vol 363 (6429) ◽  
pp. 875-880 ◽  
Author(s):  
Marcus Schewe ◽  
Han Sun ◽  
Ümit Mert ◽  
Alexandra Mackenzie ◽  
Ashley C. W. Pike ◽  
...  
Keyword(s):  
Selectivity Filter ◽  
Rational Drug Design ◽  
Related Gene ◽  
K Channels ◽  
X Ray ◽  
Voltage Gated ◽  
X Ray Crystallography ◽  
Rational Drug ◽  
Dynamics Simulations ◽  
Pore Domain

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+channels gated at their selectivity filter (SF), including many two-pore domain K+(K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2+)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+channel activators and highlight a filter gating machinery that is conserved across different families of K+channels with implications for rational drug design.

Sign in / Sign up

Export Citation Format

Share Document