Glucose-6-Phosphate Dehydrogenase from the Human Pathogen Trypanosoma cruzi Evolved Unique Structural Features to Support Efficient Product Formation

Ortiz, Cecilia; Botti, Horacio; Buschiazzo, Alejandro; Comini, Marcelo A.

doi:10.1016/j.jmb.2019.03.023

Cited by 10 publications

(14 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to other G6PDs of this family, the Ld G6PD dimer (Fig. 2a ) adopts the canonical G6PD fold with RMSD values for the dimer core domain of 2.6 Å and 2.1 Å to human ( Hs G6PD; PDBID: 2BH9) and Trypanosoma cruzi G6PD ( Tc G6PD; PDBID: 5AQ1) 26 – 29 , respectively (Fig. S3 ).…”

Section: Resultsmentioning

confidence: 64%

See 1 more Smart Citation

Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

et al. 2022

View full text Add to dashboard Cite

Since unicellular parasites highly depend on NADPH as a source for reducing equivalents, the pentose phosphate pathway, especially the first and rate-limiting NADPH-producing enzyme glucose 6-phosphate dehydrogenase (G6PD), is considered an excellent antitrypanosomatid drug target. Here we present the crystal structure of Leishmania donovani G6PD (LdG6PD) elucidating the unique N-terminal domain of Kinetoplastida G6PDs. Our investigations on the function of the N-domain suggest its involvement in the formation of a tetramer that is completely different from related Trypanosoma G6PDs. Structural and functional investigations further provide interesting insights into the binding mode of LdG6PD, following an ordered mechanism, which is confirmed by a G6P-induced domain shift and rotation of the helical N-domain. Taken together, these insights into LdG6PD contribute to the understanding of G6PDs’ molecular mechanisms and provide an excellent basis for further drug discovery approaches.

show abstract

Section: Resultsmentioning

confidence: 64%

“…However, in G6P-bound Ld G6PD structures, the position of G6P that best explains the electron density is different from that of homologous G6PD structures 26 – 29 . Compared to these structures, the G6P conformation is rotated by 180° and located in a cleft, formed by amino acids D482-A483, Q440, H250-Y251, and K254 (Fig.…”

Section: Resultsmentioning

confidence: 82%

Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The predicted and annotated sequence of G6PD from the H. pylori strain 29CaP (Identification code ALM79592.1) was used to perform a BLAST protein analysis against the Protein Data Bank (PDB), using a target database of 3D structures. The HpG6PD amino acids sequence showed the best score and the highest similarity (31%) with the G6PD of Leuconostoc mesenteriodes (PDB entry 1DPG) [ 14 ], 30% with the G6PD of Mycobacterium avium 104 (PDB entry 4LGV) [ 22 ], and 29% with the G6PD of Trypanosoma cruzi (PDB entry 6D23) [ 23 ]. To corroborate the results obtained with the BLAST protein, we used the SWISS-MODEL server [ 24 ] to identify possible molds to build the HpG6P model.…”

Section: Resultsmentioning

confidence: 99%

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

et al. 2021

View full text Add to dashboard Cite

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.

show abstract

“…Data for tetrahedral (tetr), octahedral (octa), icosahedral (icos) and non-symmetric (NS) complexes are combined for all number of subunits. (B) Assembly of a dihedral symmetry from parts of protein complexes with cyclic symmetry, glucose-6-phosphate 1-dehydrogenase (PDB: 6D23) [35]. In the representation of protein surfaces of the C 2 symmetric subcomplexes, one of the subunits is transparent to enable visualization of the interaction surface.…”

Section: Figurementioning

confidence: 99%

Modeling and Structure Determination of Homo-Oligomeric Proteins: An Overview of Challenges and Current Approaches

Gaber

Pavšič

2021

IJMS

View full text Add to dashboard Cite

Protein homo-oligomerization is a very common phenomenon, and approximately half of proteins form homo-oligomeric assemblies composed of identical subunits. The vast majority of such assemblies possess internal symmetry which can be either exploited to help or poses challenges during structure determination. Moreover, aspects of symmetry are critical in the modeling of protein homo-oligomers either by docking or by homology-based approaches. Here, we first provide a brief overview of the nature of protein homo-oligomerization. Next, we describe how the symmetry of homo-oligomers is addressed by crystallographic and non-crystallographic symmetry operations, and how biologically relevant intermolecular interactions can be deciphered from the ordered array of molecules within protein crystals. Additionally, we describe the most important aspects of protein homo-oligomerization in structure determination by NMR. Finally, we give an overview of approaches aimed at modeling homo-oligomers using computational methods that specifically address their internal symmetry and allow the incorporation of other experimental data as spatial restraints to achieve higher model reliability.

show abstract

Glucose-6-Phosphate Dehydrogenase from the Human Pathogen Trypanosoma cruzi Evolved Unique Structural Features to Support Efficient Product Formation

Cited by 10 publications

References 58 publications

Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

Modeling and Structure Determination of Homo-Oligomeric Proteins: An Overview of Challenges and Current Approaches

Contact Info

Product

Resources

About