Immediately from the outset of the COVID-19 pandemic, researchers from diverse biomedical and biological disciplines have united to study the novel pandemic virus, SARS-CoV-2. The antibody response ...to SARS-CoV-2 has been a major focus of COVID-19 research due to its clinical relevance and importance in vaccine and therapeutic development. Isolation and characterization of antibodies to SARS-CoV-2 have been accumulating at an unprecedented pace. Most of the SARS-CoV-2 neutralizing antibodies to date target the spike (S) protein receptor binding domain (RBD), which engages the host receptor ACE2 for viral entry. Here we review the binding sites and molecular features of monoclonal antibodies that target the SARS-CoV-2 RBD, including a few that also cross-neutralize SARS-CoV.
•The receptor binding domain is a major target of antibodies to SARS-CoV-2.•Neutralizing antibodies target various epitopes on the receptor binding domain.•Convergent antibody responses to SARS-CoV-2 are observed.•Cross-neutralization of SARS-CoV-2 and SARS-CoV maps to two RBD epitopes.•Antibody avidity can be crucial for neutralization potency against SARS-CoV-2.
Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 ...anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53-neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.
Neutralizing antibodies (nAbs) elicited against the receptor binding site (RBS) of the spike protein of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally less ...effective against recent variants of concern. RBS residues Glu
, Lys
, and Asn
are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on angiotensin-converting enzyme 2 binding, as well as the effects of two of these mutations (K417N and E484K) on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternative binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.
We demonstrate the synthesis of silica‐supported Ni catalyst in the presence of oleylamine (OAm) and oleic acid (OAc) as the ligand and surfactant. Compared with OAm or OAc alone, Ni/SiO2 prepared ...with OAm/OAc organic pair showed a much smaller Ni particle, a much stronger metal–support interaction (MSI), an enhanced initial conversion of both CO2 and CH4 and a prolonged stability over 16 h with zero carbon deposition. How the OAm/OAc organic pair affects the catalyst formation mechanism is proposed: OAc intimately interacts with silica by hydrogen bond formed between the carboxylic group and silanol group; OAm forms a complex with Ni and promotes the adsorption of Ni on silica through the basic property of amine ligand; amide formation between the carboxylic group of OAc and the amine group of OAm makes use of both additives; in addition, a stronger steric hindrance is given by the more complex aliphatic chain network of the pair, retarding the growth of Ni particles.
Pairwise assistance: One‐pot synthesis of Ni/SiO2 catalyst is performed by the incipient wetness impregnation method. Amide formation between oleylamine (OAm) and oleic acid (OAc) combines the advantages of OAm and OAc, strengthening the metal–support interaction. The long hydrocarbon chain network between OAm and OAc further hinders Ni agglomeration.
Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare ...antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
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•X-ray and EM structures of cross-neutralizing antibody COVA1-16 with SARS-CoV-2 RBD•COVA1-16 binding to SARS-CoV-2 RBD is dominated by CDR H3•COVA1-16 binds to a highly conserved non-RBS epitope but still competes with ACE2•IgG avidity is the key for the cross-neutralization activity of COVA1-16
COVA1-16 is a SARS-CoV-2 antibody from an individual with COVID-19 that cross-neutralizes SARS-CoV. Liu et al. reveal that COVA1-16 binds to a highly conserved epitope using a long CDR H3, where its approach angle sterically blocks ACE2 from engaging the RBS. Virus neutralization by COVA1-16 is driven by IgG avidity.
IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally ...have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.
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•Crystal structures of IGHV3-53 antibodies that frequently bind SARS-CoV-2 RBD•Binding modes (A and B) of these IGHV3-53 antibodies depend on CDR H3 length•Germline-encoded CDR H1 and H2 motifs dominate the two binding poses•CDR H3 length of IGHV3-53 antibodies is associated with light chain preference
Antibodies to the SARS-CoV-2 receptor-binding domain are commonly encoded by IGHV3-53, and most have a short CDR H3. Wu et al. show that IGHV3-53 antibodies with a long CDR H3 adopt an alternative binding mode, demonstrating that IGHV3-53 is even more versatile than previously thought in targeting SARS-CoV-2.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for ...additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
People are evolutionarily predisposed to associate threat relevant stimuli with fear or aversiveness and show an attentional bias toward threat. Attentional bias modification (ABM) has been shown to ...reduce threat biases, while quantitative reviews assessing the effectiveness of bias modification yielded inconsistent results. The current study examined the relationship between the training effect of attentional bias to threat and the type of threatening stimuli. Twenty-two participants performed a modified dot-probe task while undergoing functional near-infrared spectroscopy (fNIRS) imaging. Results indicated that there was a strong pattern of attentional avoidance among individuals in an animal but not human threat condition. Furthermore, findings from fNIRS confirmed that the influence from type of threatening stimulus would be modulated by cortical activation patterns, especially in the ventrolateral prefrontal cortices (vlPFC) and angular gyrus. Overall, these results suggest that stimulus-specific may play a major role in personalization of specific psychological interventions.
Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks ...STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced. Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription.
Mutual influences between anxiety and working memory (WM) have been extensively studied, and their curvilinear relationship resembles the classic Yerkes-Dodson law of arousal and performance. Given ...the genetic bases of both anxiety and WM, it is likely that the individual differences in the Yerkes-Dodson law of anxiety and WM may have genetic correlates. The current genome wide association study (GWAS) enrolled 1115 healthy subjects to search for genes that are potential moderators of the association between anxiety and WM. Results showed that CPNE3 rs10102229 had the strongest effect, p = 3.38E-6 at SNP level and p = 2.68E-06 at gene level. Anxiety and WM had a significant negative correlation (i.e., more anxious individuals performed worse on the WM tasks) for the TT genotype of rs10102229 (resulting in lower expression of CPNE3), whereas the correlation was positive (i.e., more anxious individuals performed better on the WM tasks) for the CC carriers. The same pattern of results was found at the gene level using gene score analysis. These effects were replicated in an independent sample (N = 330). The current study is the first to report a gene that moderates the relation between anxiety and WM and potentially provides a genetic explanation for the classic Yerkes-Dodson law.
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