Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism

DHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid dehydrogenases. In complex with E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (dihydrolipoamide dehydrogenase, DLD) components, DHTKD1 is involved in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in mitochondria. Here, the 1.9 Å resolution crystal structure of human DHTKD1 is solved in complex with the thiamine diphosphate co-factor. The structure reveals how the DHTKD1 active site is modelled upon the well characterized homologue 2-oxoglutarate (2OG) dehydrogenase but engineered specifically to accommodate its preference for the longer substrate of 2OA over 2OG. A 4.7 Å resolution reconstruction of the human DLST catalytic core is also generated by single-particle electron microscopy, revealing a 24-mer cubic scaffold for assembling DHTKD1 and DLD protomers into a megacomplex. It is further demonstrated that missense DHTKD1 variants causing the inborn error of 2-aminoadipic and 2-oxoadipic aciduria impact on the complex formation, either directly by disrupting the interaction with DLST, or indirectly through destabilizing the DHTKD1 protein. This study provides the starting framework for developing DHTKD1 modulators to probe the intricate mitochondrial energy metabolism.

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Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism

10.1101/2020.01.20.912931 ◽

2020 ◽

Cited By ~ 2

Author(s):

Gustavo A. Bezerra ◽

William R. Foster ◽

Henry J. Bailey ◽

Kevin G. Hicks ◽

Sven W. Sauer ◽

...

Keyword(s):

Crystal Structure ◽

Protein Interactions ◽

Inner Core ◽

Missense Variant ◽

Oxidative Decarboxylation ◽

Evolutionary Divergence ◽

Binary Complex ◽

Missense Mutations ◽

Mitochondrial Energy Metabolism ◽

Starting Point

ABSTRACTDHTKD1 is a lesser-studied E1 enzyme belonging to the family of 2-oxoacid dehydrogenases. DHTKD1, in complex with the E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (lipoamide dehydrogenase, DLD) components, is implicated in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in the mitochondria. Here, we solved the crystal structure of human DHTKD1 at 1.9 Å resolution in binary complex with the thiamine diphosphate (ThDP) cofactor. Our structure explains the evolutionary divergence of DHTKD1 from the well-characterized homologue 2-oxoglutarate (2OG) dehydrogenase, in its preference for the larger 2OA substrate than 2OG. Inherited DHTKD1 missense mutations cause the lysine metabolic condition 2-aminoadipic and 2-oxoadipic aciduria. Reconstruction of the missense variant proteins reveal their underlying molecular defects, which include protein destabilisation, disruption of protein-protein interactions, and alterations in the protein surface. We further generated a 5.0 Å reconstruction of the human DLST inner core by single-particle electron microscopy, revealing a 24-mer cubic architecture that serves as a scaffold for assembly of DHTKD1 and DLD. This structural study provides a starting point to develop small molecule DHTKD1 inhibitors for probing mitochondrial energy metabolism.

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Crystal structure of the catalytic core domain of the family 6 cellobiohydrolase II, Cel6A, from Humicola insolens, at 1.92 Å resolution

Biochemical Journal ◽

10.1042/0264-6021:3370297 ◽

1999 ◽

Vol 337 (2) ◽

pp. 297 ◽

Cited By ~ 30

Author(s):

Annabelle VARROT ◽

Sven HASTRUP ◽

Martin SCHÜLEIN ◽

Gideon J. DAVIES

Keyword(s):

Crystal Structure ◽

Catalytic Core Domain ◽

Catalytic Core ◽

Core Domain ◽

Humicola Insolens ◽

The Family ◽

Cellobiohydrolase Ii

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Structure of the catalytic phosphatase domain of MTMR8: implications for dimerization, membrane association and reversible oxidation

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s139900471500927x ◽

2015 ◽

Vol 71 (7) ◽

pp. 1528-1539 ◽

Cited By ~ 2

Author(s):

Ki-Young Yoo ◽

Ji Young Son ◽

Jee Un Lee ◽

Woori Shin ◽

Dong-Won Im ◽

...

Keyword(s):

Crystal Structure ◽

Disulfide Bond ◽

Bond Distance ◽

Large Family ◽

Membrane Association ◽

Structural Comparison ◽

Phosphatase Domain ◽

The Family ◽

Related Proteins ◽

Insight Into

Myotubularin-related proteins are a large family of phosphoinositide phosphatases; their activity, stability and subcellular localization are regulated by dimeric interactions with other members of the family. Here, the crystal structure of the phosphatase domain of MTMR8 is reported. Conformational deviation of the two loops that mediate interaction with the PH-GRAM domain suggests that the PH-GRAM domain interacts differently with the phosphatase domain of each MTMR member. The protein exists as a dimer with twofold symmetry, providing insight into a novel mode of dimerization mediated by the phosphatase domain. Structural comparison and mutation studies suggest that Lys255 of MTMR8 interacts with the substrate diacylglycerol moiety, similar to Lys333 of MTMR2, although the positions of these residues are different. The catalytic activity of the MTMR8 phosphatase domain is inhibited by oxidation and is reversibly reactivated by reduction, suggesting the presence of an oxidation-protective intermediate other than a disulfide bond owing to the absence of a cysteine within a disulfide-bond distance from Cys338.

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The first crystal structure of the human and the chimp CPEB3 ribozyme: a snapshot of the catalytic core reveals an unexpected fold of the HDV-like ribozymes

10.26226/morressier.5ebd45acffea6f735881aeb3 ◽

2020 ◽

Author(s):

Anna Ilaria Przytula-Mally

Keyword(s):

Crystal Structure ◽

Catalytic Core

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Faculty Opinions recommendation of Crystal structure of γ-tubulin complex protein GCP4 provides insight into microtubule nucleation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11917958.13033056 ◽

2011 ◽

Author(s):

Berl R Oakley

Keyword(s):

Crystal Structure ◽

Microtubule Nucleation ◽

Complex Protein ◽

Insight Into

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A Review of Phytochemical and Pharmacological Studies of Inula Species

Current Bioactive Compounds ◽

10.2174/1573407215666190207093538 ◽

2020 ◽

Vol 16 (5) ◽

pp. 557-567

Author(s):

Aparoop Das ◽

Anshul Shakya ◽

Surajit Kumar Ghosh ◽

Udaya P. Singh ◽

Hans R. Bhat

Keyword(s):

Bacterial Infections ◽

Chemical Constituents ◽

Valuable Insight ◽

Important Ingredient ◽

Pharmacological Activities ◽

Medicinal Uses ◽

The Family ◽

Pharmacological Studies ◽

Perennial Herbs ◽

Insight Into

Background: Plants of the genus Inula are perennial herbs of the family Asteraceae. This genus includes more than 100 species, widely distributed throughout Europe, Africa and Asia including India. Many of them are indicated in traditional medicine, e.g., in Ayurveda. This review explores chemical constituents, medicinal uses and pharmacological actions of Inula species. Methods: Major databases and research and review articles retrieved through Scopus, Web of Science, and Medline were consulted to obtain information on the pharmacological activities of the genus Inula published from 1994 to 2017. Results: Inula species are used either alone or as an important ingredient of various formulations to cure dysfunctions of the cardiovascular system, respiratory system, urinary system, central nervous system and digestive system, and for the treatment of asthma, diabetes, cancers, skin disorders, hepatic disease, fungal and bacterial infections. A range of phytochemicals including alkaloids, essential and volatile oils, flavonoids, terpenes, and lactones has been isolated from herbs of the genus Inula, which might possibly explain traditional uses of these plants. Conclusion: The present review is focused on chemical constituents, medicinal uses and pharmacological actions of Inula species and provides valuable insight into its medicinal potential.

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Crystal structure of KBSi3O8 isostructural with danburite

Mineralogical Magazine ◽

10.1180/minmag.1993.057.386.15 ◽

1993 ◽

Vol 57 (386) ◽

pp. 157-164 ◽

Cited By ~ 14

Author(s):

Mitsuyoshi Kimata

Keyword(s):

Crystal Structure ◽

Direct Method ◽

Crystal Chemical ◽

Chemical Formula ◽

Crystal Chemical Formula ◽

3 Dimensional ◽

Tetrahedral Sites ◽

Structural Types ◽

Coupled Substitution ◽

Insight Into

AbstractThe crystal structure of KBSi3O8 (orthorhombic, Pnam, with a = 8.683(1), b = 9.253(1), c = 8.272(1) Å,, V = 664.4(1) Å3, Z = 4) has been determined by the direct method applied to 3- dimensional rcflection data. The structure of a microcrystal with the dimensions 20 × 29 × 37 μm was refined to an unweightcd residual of R = 0.031 using 386 non-zero structure amplitudes. KBSi3O8 adopts a structure essentially different from recdmergneritc NaBSi3O8, with the low albite (NaAlSi3O8) structure, and isotypic with danburite CaB2Si2Os which has the same topology as paracelsian BaAl2Si2O8. The chenfical relationship between this sample and danburitc gives insight into a new coupled substitution; K+ + Si4+ = Ca2+ + B3+ in the extraframework and tetrahedral sites. The present occupancy refinement revealed partial disordering of B and Si atoms which jointly reside in two kinds of general equivalent points, T(1) and T(2) sites. Thus the expanded crystal-chemical formula can be written in the form K(B0.44Si0.56)2(B0.06Si0.94)2O8The systematic trend among crystalline compounds with the M+T3+T4+3O8 formula suggests that they exist in one of four structural types; the feldspar structures with T3+/T4+ ordered and/or disordered forms, and the paracelsian and the hollandite structures.

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Insight into an Oxidative DNA-Cleaving DNAzyme: Multiple Cofactors, the Catalytic Core Map and a Highly Efficient Variant

iScience ◽

10.1016/j.isci.2020.101555 ◽

2020 ◽

Vol 23 (10) ◽

pp. 101555 ◽

Cited By ~ 1

Author(s):

Wenqian Yu ◽

Shijin Wang ◽

Dongling Cao ◽

Hongyue Rui ◽

Chengcheng Liu ◽

...

Keyword(s):

Catalytic Core ◽

Dna Cleaving ◽

Highly Efficient ◽

Insight Into

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Crystal Chemical Relations in the Shchurovskyite Family: Synthesis and Crystal Structures of K2Cu[Cu3O]2(PO4)4 and K2.35Cu0.825[Cu3O]2(PO4)4

Crystals ◽

10.3390/cryst11070807 ◽

2021 ◽

Vol 11 (7) ◽

pp. 807

Author(s):

Ilya V. Kornyakov ◽

Sergey V. Krivovichev

Keyword(s):

Crystal Structure ◽

Crystal Structures ◽

Structural Complexity ◽

Crystal Chemical ◽

X Ray Diffraction ◽

Complexity Measures ◽

X Ray ◽

The Family ◽

Similarities And Differences ◽

Related Compounds

Single crystals of two novel shchurovskyite-related compounds, K2Cu[Cu3O]2(PO4)4 (1) and K2.35Cu0.825[Cu3O]2(PO4)4 (2), were synthesized by crystallization from gaseous phase and structurally characterized using single-crystal X-ray diffraction analysis. The crystal structures of both compounds are based upon similar Cu-based layers, formed by rods of the [O2Cu6] dimers of oxocentered (OCu4) tetrahedra. The topologies of the layers show both similarities and differences from the shchurovskyite-type layers. The layers are connected in different fashions via additional Cu atoms located in the interlayer, in contrast to shchurovskyite, where the layers are linked by Ca2+ cations. The structures of the shchurovskyite family are characterized using information-based structural complexity measures, which demonstrate that the crystal structure of 1 is the simplest one, whereas that of 2 is the most complex in the family.

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