A5065859361- Endoplasmic Reticulum Stress and Disease
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- SARS-CoV-2 and COVID-19 Research
- Mast cells and histamine
- Redox biology and oxidative stress
- Autophagy in Disease and Therapy
- Nicotinic Acetylcholine Receptors Study
- COVID-19 Clinical Research Studies
- Trypanosoma species research and implications
- Protein Structure and Dynamics
- Neuropeptides and Animal Physiology
- Genomics and Phylogenetic Studies
- Bacterial Genetics and Biotechnology
- Monoclonal and Polyclonal Antibodies Research
- Research on Leishmaniasis Studies
- Agricultural Productivity and Crop Improvement
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- Adenosine and Purinergic Signaling
- Cellular transport and secretion
- Lipid metabolism and biosynthesis
- Inflammasome and immune disorders
- ATP Synthase and ATPases Research
- Axial and Atropisomeric Chirality Synthesis
Harvard University
2017-2024
Boston VA Research Institute
2020-2024
Whitehead Institute for Biomedical Research
2023-2024
Yale University
2023
Weizmann Institute of Science
2008-2021
University of Delaware
2008
Significance Of the many receptors that were pharmacologically described during 20th century, almost all cloned by end of 1990s. A key exception is σ 2 receptor, a potential therapeutic target for diseases as diverse schizophrenia, Alzheimer’s disease, and cancer. Despite development rich pharmacopeia, unknown molecular identity receptor has crippled biological investigation. Here, we identify TMEM97, membrane protein implicated in cancer binding partner Niemann–Pick disease NPC1. Our...
Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other from screening in field, we became concerned that phospholipidosis was a shared mechanism underlying antiviral activity of many repurposed drugs. For all 23 cationic amphiphilic tested, including hydroxychloroquine, azithromycin, amiodarone, four others already clinical trials,...
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 of the σ
Form and Function The contribution of disulfide bonding to oxidative protein folding assembly, quality control, stress responses in the endoplasmic reticulum (ER) are widely recognized. In contrast, catalysis bond formation downstream ER is uncharted territory. QSOX, a Golgi-localized or secreted catalyst, was identified 1970s more recently shown be upregulated many cancers. However, physiological importance QSOX catalytic activity has been unclear. Ilani et al. (p. 74 , published online 23...
Computational design of protein function has made substantial progress, generating new enzymes, binders, inhibitors, and nanomaterials not previously seen in nature. However, the ability to backbones for function—essential exert control over all polypeptide degrees freedom—remains a critical challenge. Most previous attempts computed mainchain from scratch. Here, instead, we describe combinatorial backbone sequence optimization algorithm called AbDesign, which leverages large number...
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. necessary not sufficient development clinical disease. Currently, there are no approved pre- or post-exposure prophylactic medical countermeasures. Clinical data suggest that famotidine may mitigate disease, both mechanism action rationale dose selection remain obscure. We have investigated several plausible hypotheses activity including antiviral host-mediated...
In response to starvation, endospore-forming bacteria differentiate into stress-resistant spores that can remain dormant for years yet rapidly germinate and resume growth in nutrients. The small molecule dipicolinic acid (DPA) plays a central role both the stress resistance of spore its exit from dormancy during germination. spoVA locus is required DPA import sporulation has been implicated export germination, but molecular bases are unclear. Here, we define minimal set proteins encoded...
The flavoprotein quiescin-sulfhydryl oxidase (QSOX) rapidly inserts disulfide bonds into unfolded, reduced proteins with the concomitant reduction of oxygen to hydrogen peroxide. This study reports first heterologous expression and enzymological characterization a human QSOX1 isoform. Like QSOX isolated from avian egg white, recombinant HsQSOX1 is highly active toward ribonuclease A (RNase) dithiothreitol but shows >100-fold lower k cat/ K m for glutathione. Previous studies on led model in...
Abstract Bacteria from the orders Bacillales and Clostridiales differentiate into stress-resistant spores that can remain dormant for years, yet rapidly germinate upon nutrient sensing. How monitor nutrients is poorly understood but in most cases requires putative membrane receptors. The prototypical receptor Bacillus subtilis consists of three proteins (GerAA, GerAB, GerAC) required germination response to L-alanine. GerAB belongs Amino Acid-Polyamine-Organocation superfamily transporters....
Abstract AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies cast doubt on their direct usefulness that goal. Here, we tested unrefined AF2 models prospectively , comparing experimental hit-rates affinities from large library docking against vs same screens targeting receptors. In σ 2 5-HT2A receptors, struggled to recapitulate ligands had previously found receptors’ structures,...
Quiescin sulfhydryl oxidase (QSOX) catalyzes formation of disulfide bonds between cysteine residues in substrate proteins. Human QSOX1 is a multi-domain, monomeric enzyme containing module related to the single-domain oxidases Erv family. A partial crystal structure reveals single-chain pseudo-dimer mimicking quaternary enzymes. However, one "subunit" has lost its cofactor and catalytic activity. In QSOX evolution, further concatenation member protein isomerase family resulted an capable...
Abstract SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic medical countermeasures. Clinical data suggest that famotidine may mitigate disease, both mechanism action rationale dose selection remain obscure. We explore several plausible avenues activity including antiviral host-mediated actions. propose the principal involves on-target histamine receptor H 2...
Abstract Activation of various inflammasomes converges on the cleavage gasdermin D (GSDMD) by pro-inflammatory caspases, followed oligomerization N-terminal domain (GSDMD NT ) and assembly pores penetrating target membranes. Yet, it remained unclear what triggers conformational changes that allow membrane insertion, as methods to study pore formation in living cells were limited. We raised nanobodies specific for human GSDMD found two prevent pyroptosis IL-1β release when expressed cytosol...
Abstract Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMD NT ) oligomerize and assemble pores penetrating target membrane. As methods to study pore formation living cells are insufficient, order conformational changes, oligomerization, membrane insertion remained unclear. We have raised nanobodies (VHHs) against human GSDMD find that cytosolic expression VHH GSDMD-1 GSDMD-2 prevents oligomerization pyroptosis....
The mimivirus genome contains many genes that lack homologs in the sequence database and are thus known as ORFans. In addition, encode proteins belonging to fold families some cases fused domain-sized segments cannot be classified. One such ORFan region is present enzyme R596, a member of Erv family sulfhydryl oxidases. We determined structure variant full-length R596 observed carboxy-terminal assumes folded, compact domain, demonstrating these can stable structural units. Moreover, domain...
Abstract SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic medical countermeasures. Clinical data suggest that famotidine may mitigate disease, both mechanism action rationale dose selection remain obscure. We explore several plausible avenues activity including antiviral host-mediated actions. propose the principal involves on-target histamine receptor H 2...
Abstract The thioredoxin superfamily has expanded and diverged extensively throughout evolution such that distant members no longer show appreciable sequence homology. Nevertheless, redox‐active thioredoxin‐fold proteins functioning in diverse physiological contexts often share canonical amino acids near the active‐site (di‐)cysteine motif. Quiescin sulfhydryl oxidase 1 (QSOX1), a catalyst of disulfide bond formation secreted by fibroblasts, is multi‐domain enzyme with certain similarities...
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic medical countermeasures. Clinical data suggest that famotidine may mitigate disease, both mechanism action rationale dose selection remain obscure. We explore several plausible avenues activity including antiviral host-mediated actions. propose the principal involves on-target histamine receptor H 2...