Structures of Unliganded and Inhibitor Complexes of W168F, a Loop6 Hinge Mutant of Plasmodium falciparum Triosephosphate Isomerase: Observation of an Intermediate Position of Loop6

Eaazhisai, K.; Balaram, Hemalatha; Balaram, Padmanabhan; Murthy, M.R.N.

doi:10.1016/j.jmb.2004.08.060

Cited by 15 publications

(11 citation statements)

References 39 publications

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“…10, this means of multiple interactions with neighbouring residues. Interestingly, the only instances of loop 6 disorder in PfTIM are reported for the three crystal structures of the W168F mutant (Eaazhisai et al, 2004). Fluorescence studies in solution also confirm the absence of local motion involving Trp168 in the W11F single-tryptophan PfTIM mutant (Pattanaik et al, 2003).…”

Section: Disorder Of Loopmentioning

confidence: 70%

Structure of triosephosphate isomerase (TIM) fromMethanocaldococcus jannaschii

Gayathri

Banerjee

Vijayalakshmi

et al. 2007

Acta Crystallogr D Biol Cryst

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The crystal structure of a recombinant triosephosphate isomerase (TIM) from the archaeabacterium Methanocaldococcus jannaschii has been determined at a resolution of 2.3 A using X-ray diffraction data from a tetartohedrally twinned crystal. M. jannaschii TIM (MjTIM) is tetrameric, as suggested by solution studies and from the crystal structure, as is the case for two other structurally characterized archaeal TIMs. The archaeabacterial TIMs are shorter compared with the dimeric TIMs; the insertions in the dimeric TIMs occur in the vicinity of the tetramer interface, resulting in a hindrance to tetramerization in the dimeric TIMs. The charge distribution on the surface of the archaeal TIMs also facilitates tetramerization. Analysis of the barrel interactions in TIMs suggests that these interactions are unlikely to account for the thermal stability of the archaeal TIMs. A novelty of the unliganded structure of MjTIM is the complete absence of electron density for the loop 6 residues. The disorder of this loop could be ascribed to a missing salt bridge between residues at the N- and C-terminal ends of the loop in MjTIM.

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Section: Disorder Of Loopmentioning

confidence: 70%

Structure of triosephosphate isomerase (TIM) fromMethanocaldococcus jannaschii

Gayathri

Banerjee

Vijayalakshmi

et al. 2007

Acta Crystallogr D Biol Cryst

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“…N233 ( 232 ) is located in loop 8 and appears to be a flexible residue with a high B‐factor in all PfTIM structures. The occurrence of N233 ( 232 ) at the active site appears to hinder the movement of the ligand to the site optimal for catalysis Residue 238 ( 234 ) is A in the psychrophilic bacterium V. marinus (VmTIM); almost all other TIM sequences have an S at that position (with the exception of Pyrococcus and Methanocaldococcus ).…”

Section: Effect Of Specific Residues At Selected Positionsmentioning

confidence: 99%

A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease

et al. 2017

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Triosephosphate isomerase (TIM) is a ubiquitous enzyme, which appeared early in evolution. TIM is responsible for obtaining net ATP from glycolysis and producing an extra pyruvate molecule for each glucose molecule, under aerobic and anaerobic conditions. It is placed in a metabolic crossroad that allows a quick balance of the triose phosphate aldolase produced by glycolysis, and is also linked to lipid metabolism through the alternation of glycerol-3-phosphate and the pentose cycle. TIM is one of the most studied enzymes with more than 199 structures deposited in the PDB. The interest for this enzyme stems from the fact that it is involved in glycolysis, but also in aging, human diseases and metabolism. TIM has been a target in the search for chemical compounds against infectious diseases and is a model to study catalytic features. Until February 2017, 62% of all residues of the protein have been studied by mutagenesis and/or using other approaches. Here, we present a detailed and comprehensive recompilation of the reported effects on TIM catalysis, stability, druggability and human disease produced by each of the amino acids studied, contributing to a better understanding of the properties of this fundamental protein. The information reviewed here shows that the role of the noncatalytic residues depend on their molecular context, the delicate balance between the short and long-range interactions in concerted action determining the properties of the protein. Each protein should be regarded as a unique entity that has evolved to be functional in the organism to which it belongs. Proteins 2017; 85:1190-1211. © 2017 Wiley Periodicals, Inc.

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“…In the Trypanosoma brucei mutant (A178L) TIM structure 2V0T, its partial closure is caused by the mutation of the Loop 6 hinge residue Ala 178 to Leu . In the Plasmodium falciparum mutant (W168F) TIM structure 1VGA, the mutation of the conserved Trp 168 into Phe causes the functional Loop 6 to adapt an intermediate conformation . 2VXN and 1N55 are two closed structures that are placed further away along PC2 from the cluster of the closed structures at the bottom of the figure.…”

Section: Introductionmentioning

confidence: 99%

The critical role of the loops of triosephosphate isomerase for its oligomerization, dynamics, and functionality

Katebi

Jernigan

2013

Protein Science

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Triosephosphate isomerase (TIM) catalyzes the reaction to convert dihydroxyacetone phosphate into glyceraldehyde 3-phosphate, and vice versa. In most organisms, its functional oligomeric state is a homodimer; however, tetramer formation in hyperthermophiles is required for functional activity. The tetrameric TIM structure also provides added stability to the structure, enabling it to function at more extreme temperatures. We apply Principal Component Analysis to find that the TIM structure space is clearly divided into two groups-the open and the closed TIM structures. The distribution of the structures in the open set is much sparser than that in the closed set, showing a greater conformational diversity of the open structures. We also apply the Elastic Network Model to four different TIM structures-an engineered monomeric structure, a dimeric structure from a mesophile-Trypanosoma brucei, and two tetrameric structures from hyperthermophiles Thermotoga maritima and Pyrococcus woesei. We find that dimerization not only stabilizes the structures, it also enhances their functional dynamics. Moreover, tetramerization of the hyperthermophilic structures increases their functional loop dynamics, enabling them to function in the destabilizing environment of extreme temperatures. Computations also show that the functional loop motions, especially loops 6 and 7, are highly coordinated. In summary, our computations reveal the underlying mechanism of the allosteric regulation of the functional loops of the TIM structures, and show that tetramerization of the structure as found in the hyperthermophilic organisms is required to maintain the coordination of the functional loops at a level similar to that in the dimeric mesophilic structure.

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Structures of Unliganded and Inhibitor Complexes of W168F, a Loop6 Hinge Mutant of Plasmodium falciparum Triosephosphate Isomerase: Observation of an Intermediate Position of Loop6

Cited by 15 publications

References 39 publications

Structure of triosephosphate isomerase (TIM) fromMethanocaldococcus jannaschii

Structure of triosephosphate isomerase (TIM) fromMethanocaldococcus jannaschii

A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease

The critical role of the loops of triosephosphate isomerase for its oligomerization, dynamics, and functionality

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