Gabriel Frank - Academia.edu (original) (raw)

Papers by Gabriel Frank

Acta Crystallographica Section D Structural Biology, 2021

Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) i... more Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby prevent...

European Journal of Social Science Education and Research, 2018

Aiming to promote the social mission of higher education and their integration in Latin American ... more Aiming to promote the social mission of higher education and their integration in Latin American countries, this research has a qualitative focus and it has the objective to study the normative context and the main theoretical references for the assurance of the quality of higher education for Colombia and Ecuador, examines how the continuous improvement of higher education contributes to regional development; and proposes methodological strategies that contribute to the purpose for the regional development, in a systemic, objective, measurable and achievable in time way, like are the process management and the balanced score card for University Management Strategies and to built a public policy for Latin American Universities.

eLife, Jan 2, 2016

Restriction factors and pattern recognition receptors are important components of intrinsic cellu... more Restriction factors and pattern recognition receptors are important components of intrinsic cellular defenses against viral infection. Mammalian TRIM5α proteins are restriction factors and receptors that target the capsid cores of retroviruses and activate ubiquitin-dependent antiviral responses upon capsid recognition. Here, we report crystallographic and functional studies of the TRIM5α B-box 2 domain, which mediates higher-order assembly of TRIM5 proteins. The B-box can form both dimers and trimers, and the trimers can link multiple TRIM5α proteins into a hexagonal net that matches the lattice arrangement of capsid subunits and enables avid capsid binding. Two modes of conformational flexibility allow TRIM5α to accommodate the variable curvature of retroviral capsids. B-box mediated interactions also modulate TRIM5α's E3 ubiquitin ligase activity, by stereochemically restricting how the N-terminal RING domain can dimerize. Overall, these studies define important molecular det...

Molecular Pharmacology, 2016

The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent pump that mediates the... more The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent pump that mediates the efflux of structurally diverse drugs and xenobiotics across cell membranes, affecting drug pharmacokinetics and contributing to the development of multidrug resistance. Structural information about the conformational changes in human P-gp during the ATP hydrolysis cycle has not been directly demonstrated, although mechanistic information has been inferred from biochemical and biophysical studies conducted with P-gp and its orthologs, or from structures of other ATP-binding cassette transporters. Using single-particle cryo-electron microscopy, we report the surprising discovery that, in the absence of the transport substrate and nucleotides, human P-gp can exist in both open [nucleotide binding domains (NBDs) apart; inwardfacing] and closed (NBDs close; outward-facing) conformations. We also probe conformational states of human P-gp during the catalytic cycle, and demonstrate that, following ATP hydrolysis, P-gp transitions through a complete closed conformation to a complete open conformation in the presence of ADP.

<p>(a, b) Two orthogonal views of the superposition of gp120 polypeptides derived from the ... more <p>(a, b) Two orthogonal views of the superposition of gp120 polypeptides derived from the complex with sCD4 and 17b (PDB ID: 1GC1) and the complex with VRC01 (PDB ID: 3NGB). For clarity of visualization, only those regions of VRC01 and sCD4 that are in close proximity to gp120 are shown. The gp120 chain and sCD4 chains from the 1GC1 structure are shown in red, and yellow, respectively, while the gp120 and VRC01 chains from the 3NGB structure are shown in magenta and green, respectively.</p

PLoS Pathogens, 2012

HIV-1 infection begins with the binding of trimeric viral envelope glycoproteins (Env) to CD4 and... more HIV-1 infection begins with the binding of trimeric viral envelope glycoproteins (Env) to CD4 and a co-receptor on target Tcells. Understanding how these ligands influence the structure of Env is of fundamental interest for HIV vaccine development. Using cryo-electron microscopy, we describe the contrasting structural outcomes of trimeric Env binding to soluble CD4, to the broadly neutralizing, CD4-binding site antibodies VRC01, VRC03 and b12, or to the monoclonal antibody 17b, a co-receptor mimic. Binding of trimeric HIV-1 BaL Env to either soluble CD4 or 17b alone, is sufficient to trigger formation of the open quaternary conformation of Env. In contrast, VRC01 locks Env in the closed state, while b12 binding requires a partial opening in the quaternary structure of trimeric Env. Our results show that, despite general similarities in regions of the HIV-1 gp120 polypeptide that contact CD4, VRC01, VRC03 and b12, there are important differences in quaternary structures of the complexes these ligands form on native trimeric Env, and potentially explain differences in the neutralizing breadth and potency of antibodies with similar specificities. From cryo-electron microscopic analysis at ,9 Å resolution of a cleaved, soluble version of trimeric Env, we show that a structural signature of the open Env conformation is a three-helix motif composed of a-helical segments derived from highly conserved, non-glycosylated N-terminal regions of the gp41 trimer. The three N-terminal gp41 helices in this novel, activated Env conformation are held apart by their interactions with the rest of Env, and are less compactly packed than in the post-fusion, six-helix bundle state. These findings suggest a new structural template for designing immunogens that can elicit antibodies targeting HIV at a vulnerable, pre-entry stage.

Proceedings of the National Academy of Sciences, 2010

The molecular chaperone GroEL exists in at least two allosteric states, T and R, that interconver... more The molecular chaperone GroEL exists in at least two allosteric states, T and R, that interconvert in an ATP-controlled manner. Thermodynamic analysis suggests that the T-state population becomes negligible with increasing ATP concentrations, in conflict with the requirement for conformational cycling, which is essential for the operation of molecular machines. To solve this conundrum, we performed fluorescence correlation spectroscopy on the single-ring version of GroEL, using a fluorescent switch recently built into its structure, which turns “on,” i.e., increases its fluorescence dramatically, when ATP is added. A series of correlation functions was measured as a function of ATP concentration and analyzed using singular-value decomposition. The analysis assigned the signal to two states whose dynamics clearly differ. Surprisingly, even at ATP saturation, ∼50% of the molecules still populate the T state at any instance of time, indicating constant out-of-equilibrium cycling betwee...

Nordic Journal of Music Therapy, 2005

The main goal of the paper is to highlight the ambiguity that often lies behind the interpretatio... more The main goal of the paper is to highlight the ambiguity that often lies behind the interpretation of musical interactions. Dilemmas related to musical interaction will be presented through the course of twenty-eight sessions of music therapy with a ...

Journal of Allergy and Clinical Immunology, 1994

Loratadine, a new nonsedating histamine HI-antagonist, has been shown to inhibit immunologic rele... more Loratadine, a new nonsedating histamine HI-antagonist, has been shown to inhibit immunologic release of inflammatory mediators in addition to its HI-receptor blocking properties. After oral administration, the agent is metabolized primarily to desethoxycarbonyl-loratadine (DCL). The basic piperidine, DCL, is readily soluble in water, whereas the nonbasic urethane, loratadine, is insuficiently soluble in water for some in vitro investigations. Therefore we used the metabolite, DCL, to study its influence on in vitro leukocyte histamine release (LHR) in 24 allergic and 22 nonallergic subjects. IgE-mediated and calcium ionophore A23187induced LHR were inhibited by DCL in a dose-dependent fashion (values of drug concentration to induce 30% inhibition after stimulation with inhalant antigen, anti-IgE, concanavalin A, and calcium ionophore A23187 were 6, 8, 5, and 11 pmol/L, respectively). Higher concentrations of DCL caused mediator release in all subjects (II = 45, 30 pmol/L DC: 11% ? 2% LHR, 100 prnol/L DCL: 35% & 1% LHR), abolishing any inhibitory effect of the drug. Rapid onset of inhibition by 10 pmollL DCL was found in kinetic studies (n = 10). The inhibition of anti-IgEinduced histamine secretion was qergistically increased by simultaneous preincubation of DCL with the potent histamine Hz-agonist, FRA-19. Additional data indicate that the inhibition of LHR by DCL might involve biochemical events that occur after cellular Ca + + influx because LHR induced by N-formyl-methionyl-let@-phenylalanine or the phorbol ester, 12-0-tetradecanoyl phorbol-12-acetate, was not signiJcantly affected by DCL.

55th AIAA Aerospace Sciences Meeting, 2017

Jupiter's moon Europa is of great interest to the scientific community as evidence suggests there... more Jupiter's moon Europa is of great interest to the scientific community as evidence suggests there may be a deep liquid water ocean beneath its icy surface. To investigate the surface and subsurface, future missions to Europa will require the use of landers and/or surface probes to measure surface characteristics and investigate the potentially unique subsurface conditions beneath the ice. Ball Aerospace has begun to explore the feasibility of conducting an exploration with several small, relatively inexpensive probes as an alternative to a large and costly lander. Our team of nine undergraduate students has designed and constructed a compact, low-cost, spherical probe, which can collect, store, and transmit scientific data relevant to the study of Europa. The goal of our project was to develop and construct a TRL 4 prototype over the course of 8 months, while keeping the cost under $5000. The development focused on data collection, FPGA software development, and system integration while neglecting environmental elements, such as temperature, radiation, and shocks. Two relevant scientific instruments, a triaxial magnetometer and a Geiger counter, were selected and integrated with an avionics package, which is centered on FPGA-based command and data handling (C&DH). The FPGA is integrated with a transceiver to communicate over RF to a ground station, simulating a Europa orbiter. In order to provide the capability to observe magnetic field and radiation variations during one complete orbit of Europa about Jupiter (85 Earth hours), an independent power system was developed and integrated to sustain the probe through its entire mission of 100 hours. The power system, avionics package, science instruments, and transceiver are mounted to a custom-designed structure, contained within a 25.4 centimeter diameter sphere. The prototype collects data for a total of 100 hours, and transmits that data in 8 minute simulated passes, demonstrating the feasibility of using small, cost effective probes to explore the surface of Europa or other planetary bodies.