Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target‐based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)‐dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone analogue inhibitor 2‐((4‐fluorophenyl)amino)‐3‐hydroxynaphthalene‐1,4‐dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure‐guided design of SmDHODH inhibitors. Database The structural data are available in Protein Data Bank (PDB) database under the accession code number https://www.rcsb.org/structure/6UY4.
The transmembrane emp24 domain-containing proteins (TMED), also called p24 proteins, are members of a family of sorting receptors present in all representatives of the domain Eukarya and abundantly present in all subcompartments of the early secretory pathway, namely the endoplasmic reticulum (ER), the Golgi, and the intermediate compartment. Although essential during the bidirectional transport between the ER and the Golgi, there is still a lack of information regarding the TMEDs structure, oligomerization propensity, and biophysics of their interactions with the transport cargo. Here, we describe the first high-resolution structure of the Golgi dynamics (GOLD) domain of a TMED1 representative and its biophysical characterization in solution. The crystal structure showed a dimer formation that is also present in solution in a salt-dependent manner, suggesting that the GOLD domain can form homodimers even in the absence of the TMED1 coiled-coil region. A molecular dynamics description of the dimer stabilization, with a phylogenetic analysis of the residues important for the oligomerization and a model for the orientation towards the lipid membrane, are also presented.
Primeiramente, gostaria de agradecer a Deus por ter me dado sabedoria em cada passo do meu caminho, por ter me guiado e me auxiliado a passar pelos pontos de inflexão da minha vida, que irão me levar, sem dúvida, para mais perto do seu propósito.Agradeço aos meus pais (Vladimir e Sirlene), pois, sem eles, nenhum objetivo que já foi atingido, ou que ainda será, seria possível. Agradeço a todos os sacrifícios feitos ao longo dos anos para me propiciarem uma formação acadêmica, e por formarem meu caráter.Aos meus tios (Alfredo e Sandra), que são como segundos pais para mim e que sempre, mesmo de longe, apoiaram-me na minha jornada.À minha namorada (Virgínia), que mudou meu jeito de ver o mundo, e foi essencial ao longo do meu mestrado com todo seu carinho.Agradeço à minha orientadora Profa. Maria Cristina Nonato por ter me aceitado em seu laboratório, apesar de ter vindo de uma área completamente diferente, e por ter me dado uma "bagagem" científica imensa durante esses dois anos. Algo que jamais poderei retribuir à altura. Ao Prof. Flávio Emery, que, juntamente com o seu laboratório, foi essencial em todo o desenvolvimento do meu projeto de pesquisa. Agradeço o apoio e suporte dos meus amigos do LCP-RP, tanto cientificamente quanto pessoalmente. Mais que colegas de trabalho, vocês serão para sempre meus amigos. Agradeço também à FCFRP e à Universidade de São Paulo pelo apoio técnico e institucional que proporcionaram o desenvolvimento do meu projeto. À Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, processo n° 2019/04395-6) e ao Conselho Nacional de Desenvolvimento Tecnológico e Científico (CNPq, processo n° 132112/2019-1) pelo suporte financeiro. À John Wiley & Sons por permitir o uso do artigo "Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni". License number: 5016010292565. O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Código de Financiamento 001. "It's impossible to map out a route to your destination if you don't know where you're starting from."
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