Three new crystal structures of point mutation variants of mono TIM: conformational flexibility of loop-1, loop-4 and loop-8

Borchert, Torben V.; Kishan, KV Radha; Zeelen, J.P.; Schliebs, Wolfgang; Thanki, Narmada; Abagyan, Ruben; Jaenicke, Rainer; Wierenga, Rik K.

doi:10.1016/s0969-2126(01)00202-7

Cited by 39 publications

(49 citation statements)

References 34 publications

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“…Interestingly, a similar switch of Leu238 and Trp12 was seen in the crystal structure of another unliganded monomeric TIM (monoSS-TIM 23 ), although in this case helix A1 remains intact and loop 1 follows a path somewhat intermediate between the paths of ml1TIM and ml8bTIM (Fig. 4).…”

Section: Structure Of Loopsupporting

confidence: 60%

“…Specifically, it suggests that the buried Leu238 conformation is essential for stabilizing the structure of the monomeric folding intermediate of wildtype TIM, which is known to exist transiently. 28 -31 In this respect, the conformational heterogeneity of loop 1/loop 8 is very similar to the conformational heterogeneity seen for loop 4 in other structures of monomeric TIM: 23 two conformations of loop 4 are observed in structures of monomeric TIM. These structures also interconvert, 23 and one of them, as seen also in dimeric wild-type TIM, is stabilized (in wild-type TIM) by interactions across the dimer interface.…”

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopsupporting

confidence: 56%

“…28 -31 In this respect, the conformational heterogeneity of loop 1/loop 8 is very similar to the conformational heterogeneity seen for loop 4 in other structures of monomeric TIM: 23 two conformations of loop 4 are observed in structures of monomeric TIM. These structures also interconvert, 23 and one of them, as seen also in dimeric wild-type TIM, is stabilized (in wild-type TIM) by interactions across the dimer interface. Similarly, these monomer-monomer interactions across the wild-type dimer interface stabilize the wild-type loop 1/loop 8 conformation.…”

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopsupporting

confidence: 56%

“…Furthermore, crystallographic binding studies with monoSS-TIM have shown that in the presence of activesite ligand, Leu238 switches back to the wild-type conformation, as seen from the comparison of the crystal structures of liganded and unliganded monoSS-TIM, 23 indicating that these conformations easily interconvert. In monoSS-TIM, the sequences of loops 1 and 8 are identical to those of wild-type TIM.…”

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopmentioning

confidence: 99%

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Modeling, mutagenesis, and structural studies on the fully conserved phosphate-binding loop (Loop 8) of triosephosphate isomerase: Toward a new substrate specificity

et al. 2001

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Section: Structure Of Loopsupporting

confidence: 60%

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopsupporting

confidence: 56%

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopsupporting

confidence: 56%

Section: Conserved Ala236-ser237-leu238 Sequence Of Loopmentioning

confidence: 99%

See 2 more Smart Citations

Modeling, mutagenesis, and structural studies on the fully conserved phosphate-binding loop (Loop 8) of triosephosphate isomerase: Toward a new substrate specificity

et al. 2001

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“…Via this protocol, a 15-residue stretch (loop-3) of the trypanosomal, glycosomal TIM was changed into an 8-residue stretch. The crystal structures of several of these monomeric TIMs ( Table 1) have shown that the loops involved in dimerisation in wild-type TIM become disordered or adopt nonwild-type conformations (in particular in the unliganded structures) in the monomeric state [33,78]. For example, loop-4 is also seen to adopt a new well-ordered outwardoriented conformation in monoTIM (Fig.…”

Section: The Tim-barrel Foldmentioning

confidence: 98%

Triosephosphate isomerase: a highly evolved biocatalyst

Wierenga

Kapetaniou

Radha

2010

Cell. Mol. Life Sci.

185

227

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Triosephosphate isomerase (TIM) is a perfectly evolved enzyme which very fast interconverts dihydroxyacetone phosphate and D: -glyceraldehyde-3-phosphate. Its catalytic site is at the dimer interface, but the four catalytic residues, Asn11, Lys13, His95 and Glu167, are from the same subunit. Glu167 is the catalytic base. An important feature of the TIM active site is the concerted closure of loop-6 and loop-7 on ligand binding, shielding the catalytic site from bulk solvent. The buried active site stabilises the enediolate intermediate. The catalytic residue Glu167 is at the beginning of loop-6. On closure of loop-6, the Glu167 carboxylate moiety moves approximately 2 Å to the substrate. The dynamic properties of the Glu167 side chain in the enzyme substrate complex are a key feature of the proton shuttling mechanism. Two proton shuttling mechanisms, the classical and the criss-cross mechanism, are responsible for the interconversion of the substrates of this enolising enzyme.

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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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Three new crystal structures of point mutation variants of mono TIM: conformational flexibility of loop-1, loop-4 and loop-8

Cited by 39 publications

References 34 publications

Modeling, mutagenesis, and structural studies on the fully conserved phosphate-binding loop (Loop 8) of triosephosphate isomerase: Toward a new substrate specificity

Modeling, mutagenesis, and structural studies on the fully conserved phosphate-binding loop (Loop 8) of triosephosphate isomerase: Toward a new substrate specificity

Triosephosphate isomerase: a highly evolved biocatalyst

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

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