AMH-RII : visió molecular de problemes hormonals en la diferenciació sexual

En l'esser humà, la sisena setmana del desenvolupament embrionari marca l'inici de la diferenciació dels conductes genitals. A l'embrió mascle, es genera una hormona que produeix la degeneració dels conductes de Müller (l'hormona anti-mülleriana AMH), sense l'acció repressora de la qual, aquests conductes portarien a la generació de les trompes i la matriu. Una part important de la repressió d'aquesta hormona es basa en processos de fixació a les membranes cel·lulars, gràcies a un receptor específic (l'AMH-RII). Qualsevol error en aquests processos que involucren tant a l'hormona com al seu receptor, pot donar lloc a un singular fenomen d'hermafroditisme. Un equip d'investigadors de la UAB ha pogut elaborar una modelització tridimensional del receptor de l'hormona, que facilita l'estudi de les diferents mutacions que pot patir i, per tant, la comprensió d'aquesta estranya malaltia genètica.En el ser humano, la sexta semana del desarrollo embrionario marca el inicio de la diferenciación de los conductos genitales. En el embrión masculino, se genera una hormona que produce la degeneració de los conductos de Müller (la hormona anti-mülleriana AMH), sin la acción represora de la cual, estos conductos llevarían a la generación de las trompes y la matriz. Una parte importante de la represión de esta hormona se basa en procesos de fijación en las membranas celulares, gracias a un receptor específico (el AMH-RII). Cualquier error en estos procesos que involucran tanto a la hormona como a su receptor, puede dar lugar a un singular fenómeno de hermafroditismo. Un equipo de investigadores de la UAB ha podido elaborar una modelización tridimensional del receptor de la hormona que facilitará el estudio de las diferentes mutaciones que puede sufrir y, por lo tanto, la comprensión de esta extraña enfermedad genética

Getting Deeper into the Molecular Events of Heme Binding Mechanisms : A Comparative Multi-level Computational Study of HasAsm and HasAyp Hemophores

Altres ajuts: acord transformatiu CRUE-CSICMany biological systems obtain their activity by the inclusion of metalloporphyrins into one or several binding pockets. However, decoding the molecular mechanism under which these compounds bind to their receptors is something that has not been widely explored and is a field with open questions. In the present work, we apply computational techniques to unravel and compare the mechanisms of two heme-binding systems, concretely the HasA hemophores from Gram negative bacteria Serratia marcescens (HasAsm) and Yersinia pestis (HasAyp). Despite the high sequence identity between both systems, the comparison between the X-ray structures of their apo and holo forms suggests different heme-binding mechanisms. HasAyp has extremely similar structures for heme-free and heme-bound forms, while HasAsm presents a very large displacement of a loop that ultimately leads to an additional coordination to the metal with respect to HasAyp. We combined Gaussian accelerated molecular dynamics simulations (GaMDs) in explicit solvent and protein-ligand docking optimized for metalloligands. GaMDs were first carried out on heme-free forms of both hemophores. Then, protein-ligand dockings of the heme were performed on cluster representatives of these simulations and the best poses were then subjected to a new series of GaMDs. A series of analyses reveal the following: (1) HasAyp has a conformational landscape extremely similar between heme-bound and unbound states with no to limited impact on the binding of the cofactor, (2) HasAsm presents as a slightly broader conformational landscape in its apo state but can only visit conformations similar to the X-ray of the holo form when the heme has been bound. Such behavior results from a complex cascade of changes in interactions that spread from the heme-binding pocket to the flexible loop previously mentioned. This study sheds light on the diversity of molecular mechanisms of heme-binding and discusses the weight between the pre-organization of the receptor as well as the induced motions resulting in association. Heme-containing enzymes and proteins are important for many biological and biotechnological processes. However, very little is known about heme-binding mechanisms. To shed light on this, we report a multi-level approach combining Gaussian accelerated molecular dynamics and protein−ligand dockings optimized for metallic moieties. The protocol unveils the difference in heme recruitment between HasAsm and HasAyp hemophores and shows its possible applicability to other heme-binding proteins

Computational insight into the catalytic implication of head/tail-first orientation of arachidonic acid in human 5-lipoxygenase : consequences for the positional specificity of oxygenation

In the present work we have combined homology modeling, protein-ligand dockings, quantum mechanics/molecular mechanics calculations and molecular dynamics simulations to generate human 5-lipoxygenase (5-LOX):arachidonic acid (AA) complexes consistent with the 5-lipoxygenating activity (which implies hydrogen abstraction at the C position). Our results suggest that both the holo and the apo forms of human Stable 5-LOX could accommodate AA in a productive form for 5-lipoxygenation. The former, in a tail-first orientation, with the AA carboxylate end interacting with Lys409, gives the desired structures with C close to the Fe-OH cofactor and suitable barrier heights for H abstraction. Only when using the apo form structure, a head-first orientation with the AA carboxylate close to His600 (a residue recently proposed as essential for AA positioning) is obtained in the docking calculations. However, the calculated barrier heights for this head-first orientation are in principle consistent with 5-LOX specificity, but also with 12/8 regioselectivity. Finally, long MD simulations give support to the recent hypothesis that the Phe177 + Tyr181 pair needs to close the active site access during the chemical reaction, and suggest that in the case of a head-first orientation Phe177 may be the residue interacting with the AA carboxylate

Integrating ecosystem services and resilience in sustainable forest management

In the Anthropocene era, humanity has substantially shaped the ecosystems to meet the growing demand for provisioning ecosystem services (ES) but at the same time, it has considerably altered the functioning of the Earth system leading to completely novel and unpredictable effects. Resilience, ES and sustainability have gained tremendous popularity, over the last decades, in the scientific, policy and management arenas to address these challenges. However, less attention has been paid to the relationships between ES and resilience and how these concepts interact with sustainability. We, therefore, analyzed the concepts of ES and resilience, their relationships, strengths and weaknesses to determine how resilience and ES could be together operationalized for sustainable forest management. This analysis is based on a literature review and on interviews with leading experts in the field of resilience and/or ES. These two sources of information are complementary as the scientific literature synthetizes a long thinking process while the interviews gather main thoughts and opinions. The analysis shows that resilience and ES are closely intertwined in several ways. On one hand, resilience determines the capacity of an ecosystem to provide ES in the face of disturbances and is influenced, in turn, by human actions taken to response to changes in ES. On the other hand, resilience is defined as the ability to maintain ES. Resilience is sometimes even included in some ES classifications. Finally, these two concepts are applied together in forest management, for example to maintain a desired set of ES in the face of disturbances. The resilience approach contributes to improve the ES approach and vice versa: the resilience approach introduces the temporal dimension in the ES approach while the ES approach helps integrating the multiple dimensions, scales, methods and points of views as well as their interactions in the resilience approach. Resilience may be mandatory to ES and vice versa as a loss of resilience/ES could jeopardize ES/resilience. In conclusion, pairing ES and resilience is essential to promote policies toward sustainable forest management. However, caution should be exercised to avoid traps of one concept overriding the other

Integrating ecosystem services and resilience toward sustainability

In the Anthropocene era, humanity has considerably altered the functioning of Earth, resulting in global and inter-related social, economic and environmental crises. In response, resilience, ecosystem services (ES) and sustainability have gained tremendous popularity in the scientific, policy and management arenas. However, less attention has been paid to the relationships between ES and resilience and how these concepts interact with sustainability. We, therefore, analyzed the concepts of ES and resilience, their relationships, strengths and weaknesses to determine how resilience and ES could be together operationalized for sustainable forest management. This analysis, based on a literature review and on interviews with experts, shows that resilience and ES are closely intertwined. They meet in the social-ecological system perspective where resilience determines the capacity of the system to face disturbances and thus to provide ES and is influenced, in turn, by human actions taken to response to changes in ES. In a narrower sense, resilience is defined as the ability to maintain ES. Finally, in some ES classifications, resilience is treated as an ES among others. The resilience approach contributes to improve the ES approach and vice versa: resilience introduces the temporal dimension in ES while ES help integrating the multiple dimensions, scales, methods and points of views as well as their interactions in resilience. Resilience may be mandatory to ES and vice versa as a loss of resilience/ES could jeopardize ES/resilience. In conclusion, pairing ES and resilience is essential to promote policies toward sustainable forest management. However, caution should be exercised to avoid traps of one concept overriding the other

Investigating potential inhibitory effect of Uncaria tomentosa (Cat's Claw) against the main protease 3CL pro of SARS-CoV-2 by molecular modeling

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease M pro (also called 3CL pro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of M pro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat's claw), focusing on the inhibition of M pro. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CL pro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment

Crystal structure of c5321 : a protective antigen present in uropathogenic Escherichia coli strains displaying an SLR fold

Background: Increasing rates of antimicrobial resistance among uropathogens led, among other efforts, to the application of subtractive reverse vaccinology for the identification of antigens present in extraintestinal pathogenic E. coli (ExPEC) strains but absent or variable in non-pathogenic strains, in a quest for a broadly protective Escherichia coli vaccine. The protein coded by locus c5321 from CFT073 E. coli was identified as one of nine potential vaccine candidates against ExPEC and was able to confer protection with an efficacy of 33% in a mouse model of sepsis. c5321 (known also as EsiB) lacks functional annotation and structurally belongs to the Sel1-like repeat (SLR) family. Herein, as part of the general characterization of this potential antigen, we have focused on its structural properties. Results: We report the 1.74 Å-resolution crystal structure of c5321 from CFT073 E. coli determined by Se-Met SAD phasing. The structure is composed of 11 SLR units in a topological organisation that highly resembles that found in HcpC from Helicobacter pylori, with the main difference residing in how the super-helical fold is stabilised. The stabilising effect of disulfide bridges in HcpC is replaced in c5321 by a strengthening of the inter-repeat hydrophobic core. A metal-ion binding site, uncharacteristic of SLR proteins, is detected between SLR units 3 and 4 in the region of the inter-repeat hydrophobic core. Crystal contacts are observed between the C-terminal tail of one molecule and the C-terminal amphipathic groove of a neighbouring one, resembling interactions between ligand and proteins containing tetratricopeptide-like repeats. Conclusions: The structure of antigen c5321 presents a mode of stabilization of the SLR fold different from that observed in close homologs of known structure. The location of the metal-ion binding site and the observed crystalcontacts suggest a potential role in regulation of conformational flexibility and interaction with yet unidentified target proteins, respectively. These findings open new perspectives in both antigen design and for the identification of a functional role for this protective antigen

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention