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Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein

Journal Article · · Journal of Molecular Biology
 [1];  [1];  [1];  [2];  [1];  [1];  [3];  [3];  [4];  [4];  [2];  [1];  [5]
  1. The Scripps Research Inst., La Jolla, CA (United States)
  2. Johns Hopkins Univ., Baltimore, MD (United States). Malaria Research Inst.
  3. Atreca Inc., Redwood City, CA (United States)
  4. PATH Center for Vaccine Innovation and Access, Washington, DC (United States)
  5. The Scripps Research Inst., La Jolla, CA (United States); The Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. for Chemical Biology
Malaria vaccine candidate RTS,S/AS01 is based on the central and C-terminal regions of the circumsporozoite protein (CSP) of P. falciparum. mAb397 was isolated from a volunteer in an RTS,S/AS01 clinical trial, and it protects mice from infection by malaria sporozoites. However, mAb397 originates from the less commonly used VH3-15 germline gene compared to the VH3-30/33 antibodies generally elicited by RTS,S to the central NANP repeat region of CSP. The crystal structure of mAb397 with an NPNA4 peptide shows that the central NPNA forms a type I β-turn and is the main recognition motif. In most anti-NANP antibodies studied to date, a germline-encoded Trp is used to engage the Pro in NPNA β-turns, but here the Trp interacts with the first Asn. This “conserved” Trp, however, can arise from different germline genes and be located in the heavy or the light chain. Variation in the terminal ψ angles of the NPNA β-turns results in different dispositions of the subsequent NPNA and, hence, different stoichiometries and modes of antibody binding to rsCSP. Diverse protective antibodies against NANP repeats are therefore not limited to a single germline gene response or mode of binding.
Research Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
Bill and Melinda Gates Foundation; USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1839762
Alternate ID(s):
OSTI ID: 1834868
Journal Information:
Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 4 Vol. 432; ISSN 0022-2836
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (81)

Interactions with Aromatic Rings in Chemical and Biological Recognition journal March 2003
Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures journal April 2011
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
On the nature of antibody combining sites: Unusual structural features that may confer on these sites an enhanced capacity for binding ligands journal January 1990
Satisfying Hydrogen Bonding Potential in Proteins journal May 1994
C-h⋯π-interactions in proteins journal March 2001
Structure, function and properties of antibody binding sites journal January 1991
The molecular surface package journal June 1993
To Migrate or to Invade: Those Are the Options journal November 2007
Peek-Peak-Pique: Repeating Motifs of Subtle Variance Are Targets for Potent Malaria Antibodies journal May 2018
Endotoxin reduction in monoclonal antibody preparations using arginine journal September 2007
Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination journal February 2018
Automated molecular microscopy: The new Leginon system journal July 2005
DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal May 2009
Structural analysis of B-cell epitopes in antibody:protein complexes journal January 2013
Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control? journal February 2011
The RTS,S malaria vaccine journal July 2010
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial journal July 2015
RTS,S malaria vaccine could provide major public health benefits journal August 2019
Spread of a single multidrug resistant malaria parasite lineage ( PfPailin ) to Vietnam journal October 2017
Emergence of Plasmodium falciparum triple mutant in Cambodia journal December 2017
Circumsporozoite protein is required for development of malaria sporozoites in mosquitoes journal January 1997
Immune mechanisms in malaria: new insights in vaccine development journal February 2013
A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite journal March 2018
Comparative population structure of Plasmodium falciparum circumsporozoite protein NANP repeat lengths in Lilongwe, Malawi journal June 2013
Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children journal June 2016
Unexpected fold in the circumsporozoite protein target of malaria vaccines journal April 2012
The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host journal January 2011
Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study journal June 2016
PlasmoDB: the Plasmodium genome resource. A database integrating experimental and computational data journal January 2003
PIGSPro: prediction of immunoGlobulin structures v2 journal May 2017
Phaser crystallographic software journal July 2007
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
FEM: feature-enhanced map journal February 2015
Vaccine candidate discovery for the next generation of malaria vaccines journal July 2017
Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria journal June 1985
Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum journal August 1984
DNA cloning of Plasmodium falciparum circumsporozoite gene: amino acid sequence of repetitive epitope journal August 1984
Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope journal June 2018
Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages journal December 2019
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010
Automated Identification of Complementarity Determining Regions (CDRs) Reveals Peculiar Characteristics of CDRs and B Cell Epitopes journal October 2008
Sequence-specific determination of protein and peptide concentrations by absorbance at 205 nm: Sequence-Specific Protein Concentration at 205 nm journal April 2013
Structures of N-termini of helices in proteins: Structures of N-termini of helices journal January 1997
Structure validation by Cα geometry: ϕ,ψ and Cβ deviation journal January 2003
Structure, function and properties of antibody binding sites journal January 1991
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial journal July 2015
RTS,S malaria vaccine pilots in three African countries journal April 2019
Spread of a single multidrug resistant malaria parasite lineage ( PfPailin ) to Vietnam journal October 2017
Emergence of Plasmodium falciparum triple mutant in Cambodia journal December 2017
Antigen–antibody interface properties: Composition, residue interactions, and features of 53 non-redundant structures journal March 2012
Heparan Sulfate Proteoglycans Provide a Signal to Plasmodium Sporozoites to Stop Migrating and Productively Invade Host Cells journal November 2007
Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies journal December 2017
Structure of the Complex between HER2 and an Antibody Paratope Formed by Side Chains from Tryptophan and Serine journal September 2010
Appion: An integrated, database-driven pipeline to facilitate EM image processing journal April 2009
Gctf: Real-time CTF determination and correction journal January 2016
Conformational preferences of synthetic peptides derived from the immunodominant site of the circumsporozoite protein of Plasmodium falciparum by proton NMR journal August 1990
Protection against malaria at 1 year and immune correlates following PfSPZ vaccination journal May 2016
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein journal March 2018
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination journal February 2017
Antibodies against Plasmodium falciparum malaria at the molecular level journal August 2019
Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine journal April 2017
Crystal structure of an NPNA-repeat motif from the circumsporozoite protein of the malaria parasite Plasmodium falciparum journal January 2006
Four-Year Efficacy of RTS,S/AS01E and Its Interaction with Malaria Exposure journal March 2013
Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children journal June 2016
Origins of specificity and affinity in antibody–protein interactions journal June 2014
Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein journal November 2017
A Binding Site for Highly Sulfated Heparan Sulfate Is Identified in the N Terminus of the Circumsporozoite Protein: SIGNIFICANCE FOR MALARIAL SPOROZOITE ATTACHMENT TO HEPATOCYTES journal March 2004
Phaser crystallographic software journal July 2007
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions journal November 2004
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
FEM: feature-enhanced map journal February 2015
Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts journal October 2018
Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine journal August 2013
The Antibody Response to Plasmodium falciparum : Cues for Vaccine Design and the Discovery of Receptor-Based Antibodies journal April 2019
Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria journal January 2010
Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages collection January 2019
Pi-Pi contacts are an overlooked protein feature relevant to phase separation journal February 2018

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