Structural insights into the dimer-tetramer transition of FabI from Bacillus anthracis

Kim, Hyun Tae; Kim, Sulhee; Na, Byeong Kwan; Chung, Jiwoung; Hwang, Eunha; Hwang, Kwang Yeon

doi:10.1016/j.bbrc.2017.09.084

Cited by 7 publications

(7 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Later, it was shown that the oligomeric transition is coupled to ligand binding in Sa FabI, which is supported by the increased ligand affinity depending on FabI’s oligomerization state . The link between interface stabilization and ligand binding was finally established for Sa FabI and Ba FabI, where inactive dimers displayed a large H5 inward bending (55°), blocking the NADH binding site. This is supported by the Sa FabI mutant Met99Thr, located at the loop between H4/5 and the loop with twin tyrosine residues, which induces a decrease in AFN activity by 2-fold but not TCL …”

Section: Discussionmentioning

confidence: 95%

Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

Shevchenko

Lima

Cino

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The enzyme enoyl-ACP reductase (FabI) is the limiting step of the membrane’s fatty acid biosynthesis in bacteria and a druggable target for novel antibacterial agents. The FabI active form is a homotetramer, which displays the highest affinity to inhibitors. Herein, molecular dynamics studies were carried out using the structure of FabI in complex with known inhibitors to investigate their effects on tetramerization. Our results suggest that multimerization is essential for the integrity of the catalytic site and that inhibitor binding enables the multimerization by stabilizing the substrate binding loop (SBL, L:195-200) coupled with changes in the H4/5 (QR interface). We also observed that AFN-1252 (naphtpyridinone derivative) promotes unique conformational changes affecting monomer–monomer interfaces. These changes are induced by AFN-1252 interaction with key residues in the binding sites (Ala95, Tyr146, and Tyr156). In addition, the analysis of water trajectories indicated that AFN-1252 complexes allow more water molecules to enter the binding site than triclosan and MUT056399 complexes. FabI–AFN-1252 simulations show accumulation of water molecules near the Tyr146/147 pocket, which can become a hotspot to the design of novel FabI inhibitors.

show abstract

Section: Discussionmentioning

confidence: 95%

Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

Shevchenko

Lima

Cino

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…In the original group E, the concentration of NO 3 – -N decreased at 12–36 h, and the corresponding 24–48 h NAR increased. The 6–36 h NIR increased, indicating that denitrification continued to increase at 12–36 h and that nitrification and denitrification coexisted at 12–24 h ( Kim et al, 2017 ; Zhang et al, 2020 ). At 12 h, the proportion of Planctomycetes increased in groups C, D, and E. In comparison, the percentage of Planctomycetes increased at 24 h in groups A and B.…”

Section: Discussionmentioning

confidence: 99%

Effective mechanisms of water purification for nitrogen-modified attapulgite, volcanic rock, and combined exogenous microorganisms

et al. 2022

View full text Add to dashboard Cite

The study tested the water purification mechanism of the combination of microorganisms and purification materials via characteristic, enzymatic, and metagenomics methods. At 48 h, the removal rates of total nitrogen, total phosphorous, and Mn chemical oxygen demand in the combination group were 46.91, 50.93, and 65.08%, respectively. The alkaline phosphatase (AKP) activity increased during all times tested in the volcanic rock, Al@TCAP, and exogenous microorganism groups, while the organophosphorus hydrolase (OPH), dehydrogenase (DHO), and microbial nitrite reductase (NAR) activities increased at 36-48, 6-24, and 36-48 h, respectively. However, the tested activities only increased in the combination groups at 48 h. Al@TCAP exhibits a weak microbial loading capacity, and the Al@TCAP removal is primarily attributed to adsorption. The volcanic rock has a sufficient ability to load microorganisms, and the organisms primarily perform the removal for improved water quality. The predominant genera Pirellulaceae and Polynucleobacter served as the sensitive biomarkers for the treatment at 24, 36-48 h. Al@TCAP increased the expression of Planctomycetes and Actinobacteria, while volcanic rock increased and decreased the expression of Planctomycetes and Proteobacteria. The growth of Planctomycetes and the denitrification reaction were promoted by Al@TCAP and the exogenous microorganisms. The purification material addition group decreased the expression of Hyaloraphidium, Chytridiomycetes (especially Hyaloraphidium), and Monoblepharidomycetes and increased at 36-48 h, respectively. Ascomycota, Basidiomycota, and Kickxellomycota increased in group E, which enhanced the nitrogen cycle through microbial enzyme activities, and the growth of the genus Aspergillus enhanced the phosphorous purification effect.

show abstract

“…The signature Tyr-(Xaa)6-Lys FabI catalytic dyad places the active site in the same location as other FabIs (8,9). FabI is a dimer of dimers with three molecular two-fold noncrystallographic symmetry axes (P, Q, and R) along the subunit interfaces (37)(38)(39) (Fig. 5B).…”

Section: The Affabi Crystal Structurementioning

confidence: 95%

“…FabI tetramers are stabilized by extensive intermolecular interactions along the protomer interfaces with conserved dimerization and tetramerization interfaces (37,38,45). Like clade 1-3 FabIs, AfFabI dimerization occurs along the P axis interface and consists of interacting helices 8 and strands 7 linking the A/B or C/D protomers (Fig.…”

Section: The Affabi Crystal Structurementioning

confidence: 99%

The genome of a Bacteroidetes inhabitant of the human gut encodes a structurally distinct enoyl-acyl carrier protein reductase (FabI)

Radka

Frank

Yao

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Enoyl-acyl carrier protein reductase (FabI) catalyzes a rate-controlling step in bacterial fatty-acid synthesis and is a target for antibacterial drug development. A phylogenetic analysis shows that FabIs fall into four divergent clades. Members of clades 1–3 have been structurally and biochemically characterized, but the fourth clade, found in members of phylum Bacteroidetes, is uncharacterized. Here, we identified the unique structure and conformational changes that distinguish clade 4 FabIs. Alistipes finegoldii is a prototypical Bacteroidetes inhabitant of the gut microbiome. We found that A. finegoldii FabI (AfFabI) displays cooperative kinetics and uses NADH as a cofactor, and its crystal structure at 1.72 Å resolution showed that it adopts a Rossmann fold as do other characterized FabIs. It also disclosed a carboxyl-terminal extension that forms a helix–helix interaction that links the protomers as a unique feature of AfFabI. An AfFabI·NADH crystal structure at 1.86 Å resolution revealed that this feature undergoes a large conformational change to participate in covering the NADH-binding pocket and establishing the water channels that connect the active site to the central water well. Progressive deletion of these interactions led to catalytically compromised proteins that fail to bind NADH. This unique conformational change imparted a distinct shape to the AfFabI active site that renders it refractory to a FabI drug that targets clade 1 and 3 pathogens. We conclude that the clade 4 FabI, found in the Bacteroidetes inhabitants of the gut, have several structural features and conformational transitions that distinguish them from other bacterial FabIs.

show abstract

Structural insights into the dimer-tetramer transition of FabI from Bacillus anthracis

Cited by 7 publications

References 26 publications

Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

Effective mechanisms of water purification for nitrogen-modified attapulgite, volcanic rock, and combined exogenous microorganisms

The genome of a Bacteroidetes inhabitant of the human gut encodes a structurally distinct enoyl-acyl carrier protein reductase (FabI)

Contact Info

Product

Resources

About