Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand

Geldenhuys, Werner J.; Long, Timothy E.; Saralkar, Pushkar; Iwasaki, Toshio; Nunez, R.; Nair, R.; Konkle, Mary E.; Menze, Michael A.; Pinti, Mark V.; Hollander, John M.; Hazlehurst, Lori A.; Robart, Aaron R.

doi:10.1038/s42004-019-0172-x

Cited by 26 publications

(45 citation statements)

References 29 publications

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“…respiration) and decreased cell proliferation similar to what was found with reduced NEET proteins expression [12]. To date, despite the critical role that NEET proteins play in many human diseases, only few efforts were directed at the development of new ligand and drugs that target these proteins [5,73,83,109].…”

Section: Neet Proteins As Drug Targetsmentioning

confidence: 68%

“…9) was also shown to bind to mNT and stabilize its [2Fe-2S] cluster. The first furosemide-mNT co-crystal structure recently confirmed that furosemide binds to the junction between the NEET protein [2Fe-2S] cluster-binding domain and the β-cap domain [83]. This structure laid a critical molecular structural foundation for further development of rational stabilizer designs targeting NEET protein by the "cluster stabilizer mechanism".…”

Section: Neet Proteins As Drug Targetsmentioning

confidence: 92%

“…The function of NEET proteins in mitochondrial morpho-dynamism (see above), could therefore affect mitochondrial dysfunction associated with different metabolic diseases such as obesity and type 2 diabetes. NEET proteins may therefore be novel targets for drug development and treatment of metabolic abnormalities including, obesity and type 1 and type 2 diabetes [49,83].…”

Section: Ivb Neet Proteins and Obesitymentioning

confidence: 99%

“…Using nanotechnology to encapsulate, NL-1, into poly (lactic-co-glycolic acid) nanoparticles can further overcome low solubility of the molecule and enable it to cross the brain blood barriers (BBB) [113]. These strategies laid the basis for the research and development of drugs targeting NEET proteins [83,113]. Takahashi et al [109] designed and synthesized a PGZ derivative, named TT01001 that interacts with mNT specifically without interacting with PPAR-γ, originally targeted by PGZ [6].…”

Section: Neet Proteins As Drug Targetsmentioning

confidence: 99%

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The balancing act of NEET proteins: Iron, ROS, calcium and metabolism

Nechushtai

Karmi

Zuo

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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NEET proteins belong to a highly conserved group of [2Fe-2S] proteins found across all kingdoms of life. Due to their unique 2Fe-2S cluster structure, they play a key role in the regulation of many different redox and oxidation processes. In eukaryotes, NEET proteins are localized to the mitochondria, ER and the membranes connecting these organelles (MAM), and are involved in the control of multiple processes, ranging from autophagy and apoptosis to ferroptosis, oxidative stress, cell proliferation, redox control and iron and iron-sulfur homeostasis. Through their different functions and interactions with key proteins such as VDAC and Bcl-2, NEET proteins coordinate different mitochondrial, MAM, ER and cytosolic processes and functions and regulate major signaling molecules such as calcium and reactive oxygen species. Owing to their central role in cells, NEET proteins are associated with numerous human maladies including cancer, metabolic diseases, diabetes, obesity, and neurodegenerative diseases. In recent years, a new and exciting role for NEET proteins was uncovered, i.e., the regulation of mitochondrial dynamics and morphology. This new role places NEET proteins at the forefront of studies into cancer and different metabolic diseases, both associated with the regulation of mitochondrial dynamics. Here we review recent studies focused on the evolution, biological role, and structure of NEET proteins, as well as discuss different studies conducted on NEET protein function using transgenic organisms. We further discuss the different strategies used in the development of drugs that target NEET proteins, and link these with the different roles of NEET proteins in cells.

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Section: Neet Proteins As Drug Targetsmentioning

confidence: 68%

Section: Neet Proteins As Drug Targetsmentioning

confidence: 92%

Section: Ivb Neet Proteins and Obesitymentioning

confidence: 99%

Section: Neet Proteins As Drug Targetsmentioning

confidence: 99%

See 2 more Smart Citations

The balancing act of NEET proteins: Iron, ROS, calcium and metabolism

Nechushtai

Karmi

Zuo

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…1). These are built from the 12 X-ray structures of human NEET proteins (mNT [22,35,[40][41][42][43][44] and NAF-1 [45,46], Table S1). In 1, the [2Fe-2S] cluster and the side chains of ligated three cysteine residues and one histidine residue were included.…”

Section: Qm Calculationsmentioning

confidence: 99%

The two redox states of the human NEET proteins’ [2Fe–2S] clusters

et al. 2021

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The NEET proteins constitute a unique class of [2Fe–2S] proteins. The metal ions bind to three cysteines and one histidine. The proteins’ clusters exist in two redox states; the oxidized protein (containing two FeIII ions) can transfer the cluster to apo-acceptor protein(s), while the reduced form (containing one ferrous ion) remains bound to the protein frame. Here, we perform in silico and in vitro studies on human NEET proteins in both reduced and oxidized forms. Quantum chemical calculations on all available human NEET proteins structures suggest that reducing the cluster weakens the Fe–NHis and Fe–SCys bonds, similar to what is seen in other Fe–S proteins (e.g., ferredoxin and Rieske protein). We further show that the extra electron in the [2Fe–2S]+ clusters of one of the NEET proteins (mNT) is localized on the His-bound iron ion, consistently with our previous spectroscopic studies. Kinetic measurements demonstrate that the mNT [2Fe–2S]+ is released only by an increase in temperature. Thus, the reduced state of human NEET proteins [2Fe–2S] cluster is kinetically inert. This previously unrecognized kinetic inertness of the reduced state, along with the reactivity of the oxidized state, is unique across all [2Fe–2S] proteins. Finally, using a coevolutionary analysis, along with molecular dynamics simulations, we provide insight on the observed allostery between the loop L2 and the cluster region. Specifically, we show that W75, R76, K78, K79, F82 and G85 in the latter region share similar allosteric characteristics in both redox states. Graphic abstract

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Identifying Protective Drugs for Parkinson's Disease in Health‐Care Databases Using Machine Learning

et al. 2022

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Background Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. Objective We aimed at detecting potentially protective associations between marketed drugs and PD through a large‐scale automated screening strategy. Methods We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case–control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2‐year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. Results Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC‐C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). Conclusions We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML‐based signal detection algorithms for identifying drugs inversely associated with PD risk in health‐care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand

Cited by 26 publications

References 29 publications

The balancing act of NEET proteins: Iron, ROS, calcium and metabolism

The balancing act of NEET proteins: Iron, ROS, calcium and metabolism

The two redox states of the human NEET proteins’ [2Fe–2S] clusters

Identifying Protective Drugs for Parkinson's Disease in Health‐Care Databases Using Machine Learning

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