A5103132366- Biochemical Acid Research Studies
- Genetic Neurodegenerative Diseases
- Microbial metabolism and enzyme function
- Biochemical and Molecular Research
- Metabolism and Genetic Disorders
- Folate and B Vitamins Research
- Porphyrin Metabolism and Disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Metalloenzymes and iron-sulfur proteins
- Glycogen Storage Diseases and Myoclonus
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- Radioactive element chemistry and processing
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Alcoholism and Thiamine Deficiency
- Genomics and Rare Diseases
- Enzyme Structure and Function
- Genomics and Chromatin Dynamics
- Autophagy in Disease and Therapy
- RNA Research and Splicing
University of Oxford
2017-2024
Max Planck Institute of Biophysics
2024
Goethe University Frankfurt
2023-2024
Institute of Biochemistry
2024
Genomics (United Kingdom)
2017-2020
Genomics England
2018-2020
European Molecular Biology Laboratory
2019
University of Bristol
2017
Abstract The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing cysteine desulfurase NFS1 that activated by frataxin (FXN), scaffold protein ISCU, accessory ISD11, and acyl-carrier ACP. Deficiency FXN leads to loss-of-function neurodegenerative disorder Friedreich’s ataxia (FRDA). Here 3.2 Å resolution cryo-electron microscopy structure FXN-bound active human complex, two copies...
Abstract Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries re-engineered native proteins has proved challenging. Wholesale modification is potentially compromised by their intrinsic complexity, which often obscures underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity combining a robust de novo designed chassis with design process that avoids atomistic mimicry...
The condensin protein complex plays a key role in the structural organization of genomes. How ATPase activity its SMC subunits drives large-scale changes chromosome topology has remained unknown. Here we reconstruct, at near-atomic resolution, sequence events that take place during cycle. We show ATP binding induces conformational switch Smc4 head domain releases hitherto undescribed interaction with Ycs4 HEAT-repeat subunit and promotes engagement Smc2 into an asymmetric heterodimer....
The autophagy-lysosome system directs the degradation of a wide variety cargo and is also involved in tumor progression. Here, we show that immunity-related GTPase family Q protein (IRGQ), an uncharacterized to date, acts quality control major histocompatibility complex class I (MHC I) molecules. IRGQ misfolded MHC toward lysosomal through its binding mode GABARAPL2 LC3B. In absence IRGQ, free heavy chains do not only accumulate cell but are transported surface, thereby promoting immune...
Abstract Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production glutathione, cysteine, and hydrogen sulfide. Appended to conserved catalytic domain human CBS a regulatory that modulates activity by S -adenosyl- L -methionine (SAM) promotes oligomerisation. Here we show using cryo-electron microscopy full-length in basal SAM-bound activated states polymerises as filaments mediated loop. In state, sterically block active site, resulting...
Abstract 5′-aminolevulinate synthase (ALAS) catalyzes the first step in heme biosynthesis, generating from glycine and succinyl-CoA. Inherited frameshift indel mutations of human erythroid-specific isozyme ALAS2, within a C-terminal (Ct) extension its catalytic core that is only present higher eukaryotes, lead to gain-of-function X-linked protoporphyria (XLP). Here, we report ALAS2 crystal structure, revealing Ct-extension folds onto core, sits atop active site, precludes binding substrate...
DHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid dehydrogenases. In complex with E2 (dihydrolipoamide succinyltransferase, DLST) and E3 dehydrogenase, DLD) components, involved in lysine tryptophan catabolism by catalysing oxidative decarboxylation 2-oxoadipate (2OA) mitochondria. Here, 1.9 Å resolution crystal structure human solved thiamine diphosphate co-factor. The reveals how active site modelled upon well characterized homologue 2-oxoglutarate (2OG) dehydrogenase but...
The majority of clinical degrader candidates utilize an immunomodulatory imide drug (IMiD)-based derivative, that directs their target substrate to the E3 ligase receptor Cereblon (CRBN), however, concomitant neo-substrate degradation by IMiDs often results in severe off-target effects. Further biophysical screening is needed discover CRBN binders might overcome these safety concerns, but previously reported protein constructs suffer significant limitations reduce applicability as tools for...
Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism. Autosomal recessive pathogenic variations MCEE reportedly cause methylmalonic aciduria (MMAuria) eleven patients. We investigated a cohort 150 individuals suffering from MMAuria unknown origin, identifying ten new patients with MCEE. Nine were homozygous for known nonsense variation p.Arg47* (c.139C > T), one novel missense p.Ile53Arg (c.158T G). To...
Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life involved in the production glutathione, cysteine, and hydrogen sulphide 1–4 . Human CBS appends to its conserved catalytic domain a regulatory that modulates activity by S-adenosyl-L-methionine (SAM) promotes oligomerization 5–12 , however molecular basis unknown. Here we show using cryo-electron microscopy full-length human basal SAM-bound activated states polymerises as filaments mediated loop. In...
The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation homogenous and cost-efficient expression in E. coli. Extensive profiling construct shows it be "best both worlds"...
Abstract Cobalamin, commonly known as vitamin B 12 , is an essential micronutrient for humans because of its role enzyme cofactor. Cobalamin one over a dozen structurally related compounds – cobamides that are found in food and produced by microorganisms the human gut. Very little about how different affect -dependent metabolism cells. Here, we test vitro diverse cobamide cofactors function methylmalonyl-CoA mutase (MMUT), two cobalamin-dependent enzymes humans. We find that, although...
Abstract Iron-sulfur clusters (ISC) are essential in all life forms and carry out many crucial cellular functions. The core machinery for de novo ISC biosynthesis, located the mitochondria matrix, is a five-protein complex containing cysteine desulfurase NFS1 that activated by frataxin (FXN), scaffold protein ISCU, accessory ISD11, acyl-carrier ACP. Deficiency FXN leads to loss-of-function neurodegenerative disorder Friedreich’s ataxia (FRDA). Recently crystal structures depicting inactive...
ABSTRACT DHTKD1 is a lesser-studied E1 enzyme belonging to the family of 2-oxoacid dehydrogenases. DHTKD1, in complex with E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (lipoamide dehydrogenase, DLD) components, implicated lysine tryptophan catabolism by catalysing oxidative decarboxylation 2-oxoadipate (2OA) mitochondria. Here, we solved crystal structure human at 1.9 Å resolution binary thiamine diphosphate (ThDP) cofactor. Our explains evolutionary divergence from...
Abstract Human methylmalonyl-CoA epimerase ( MCEE ) catalyzes the interconversion of D-methylmalonyl-CoA and L-methylmalonyl-CoA in propionate catabolism. Autosomal recessive mutations reportedly cause methylmalonic aciduria (MMAuria) eleven patients. We investigated a cohort 150 individuals suffering from MMAuria unknown origin, identifying ten new patients with . Nine were homozygous for known nonsense mutation p.Arg47* (c.139C>T), one novel missense p.Ile53Arg (c.158T>G). To...