Crystal Structure of a Neutralizing Human IgG Against HIV-1: A Template for Vaccine Design

Saphire, Erica Ollmann; Parren, Paul W.H.I.; Pantophlet, Ralph; Zwick, Michael B.; Morris, Garrett M.; Rudd, Pauline M.; Dwek, Raymond A.; Stanfield, Robyn L.; Burton, Dennis R.; Wilson, Ian A.

doi:10.1126/science.1061692

Cited by 849 publications

(783 citation statements)

References 37 publications

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“…1998), 1HZH (Saphire et al. 2001) for investigating both antibody–antigen interactions and antibody–receptor interactions. In particular, here we investigated the influence of the glycosylation/fucosylation on the interactions between the Fc γ RIIIA and the Fc fragments within the two in‐house developed chimera mAb models Chimera 1A and Chimera 2 .…”

Section: Discussionmentioning

confidence: 99%

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Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.

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Section: Discussionmentioning

confidence: 99%

“…1998), and 1HZH (Saphire et al. 2001) and of several mAb fragments in complex with their interactors, that is, a human IgG1–Fc fragment in complex with its receptor, Fc γ RIII (see 3SGJ, 3SGK) (Sondermann et al. 2000), and the infliximab Fab fragment in complex with TNF α (see 4G3Y) (Liang et al.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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“…This hydrodynamic size is in accordance with the value predicted by using the Hydropro software 53 on the crystal structure of an intact IgG1 mAb (PDB ID 1hzh). 54 Refractive index, refractive index increment, and viscosity…”

Section: Static and Dynamic Light Scatteringmentioning

confidence: 99%

Aggregation of a multidomain protein: A coagulation mechanism governs aggregation of a model IgG1 antibody under weak thermal stress

et al. 2010

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Using an IgG1 antibody as a model system, we have studied the mechanisms by which multidomain proteins aggregate at physiological pH when incubated at temperatures just below their lowest thermal transition. In this temperature interval, only minor changes to the protein conformation are observed. Light scattering consistently showed two coupled phases: an initial fast phase followed by several hours of exponential growth of the scattered intensity. This is the exact opposite of the lagtime behavior typically observed in protein fibrillation. Dynamic light scattering showed the rapid formation of an aggregate species with a hydrodynamic radius of about 25 nm, which then increased in size throughout the experiment. Theoretical analysis of our light scattering data showed that the aggregate number density goes through a maximum in time providing compelling evidence for a coagulation mechanism in which aggregates fuse together. Both the analysis as well as size-exclusion chromatography of incubated samples showed the actual increase in aggregate mass to be linear and reach saturation long before all molecules had been converted to aggregates. The CH2 domain is the only domain partly unfolded in the temperature interval studied, suggesting a pivotal role of this least stable domain in the aggregation process. Our results show that for multidomain proteins at temperatures below their thermal denaturation, transient unfolding of a single domain can prime the molecule for aggregation, and that the formation of large aggregates is driven by coagulation.

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“…[9,107] From the neutralizing antibody IgG b12, a peptide domain known as CDR H3 was identified to be involved in binding to the gp120 on HIV-1 and thereby blocking the interaction with CD4 receptor on the host cell and causing neutralization of the virus. [108] Using a consecutive ester-amide/thiol-ene postpolymerization modification strategy, [109] a library of polymer conjugates was prepared that presented multiple copies of the CDR H3 peptide via thioether side chains (35). HIV-1 inhibitory properties with HIV-1 HXB2 on HOS CCR5 cells revealed that midsized polymer conjugates displayed the highest antiviral efficacy (IC 50 ¼ 2-3 Â 10 À6 M total peptide content) while lower efficacies were determined for the copolymers with high and low molecular weight (IC 50 % 10 Â 10 À6 M total peptide content).…”

Section: Polymer Conjugated Entry and Fusion Inhibitorsmentioning

confidence: 99%

Polymeric Anti‐HIV Therapeutics

Danial

Klok

2014

Macromolecular Bioscience

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The scope of this review is to highlight the application of polymer therapeutics in an effort to curb the transmission and infection of the human immunodeficiency virus (HIV). Following a description of the HIV life cycle, the use of approved antiretroviral drugs that inhibit critical steps in the HIV infection process is highlighted. After that, a comprehensive overview of the structure and inhibitory properties of polymeric anti‐HIV therapeutic agents is presented. This overview will include inhibitors based on polysaccharides, synthetic polymers, dendritic polymers, polymer conjugates as well as polymeric DC‐SIGN antagonists. The review will conclude with a section that discusses the applications of polymers and polymer conjugates as systemic and topical anti‐HIV therapeutics.

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Crystal Structure of a Neutralizing Human IgG Against HIV-1: A Template for Vaccine Design

Cited by 849 publications

References 37 publications

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Aggregation of a multidomain protein: A coagulation mechanism governs aggregation of a model IgG1 antibody under weak thermal stress

Polymeric Anti‐HIV Therapeutics

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