Closed Conformation of the Active Site Loop of Rabbit Muscle Triosephosphate Isomerase in the Absence of Substrate: Evidence of Conformational Heterogeneity

Aparício, Ricardo; Ferreira, Sérgio T.; Polikarpov, Igor

doi:10.1016/j.jmb.2003.10.022

Cited by 46 publications

(54 citation statements)

References 80 publications

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“…Nevertheless, its region T38-G43 proves to be the most flexible one of the apoprotein, with motions on two time scales, subnanosecond and nanosecond, suggesting the presence of an ensemble of conformers in rapid equilibrium with a lowenergy barrier. 24 Consistently, backbone RMSDs greater than 1 Å are observed in this region. NMR dynamics parameters of GaPPIX-HasA and crystallographic B-factors of FePPIX-HasA (PDB code 1B2V) show that in loaded HasA, loop L1 is rigid.…”

Section: Conformational and Dynamic Changes Upon Heme Bindingsupporting

confidence: 54%

Comparative Analysis of Structural and Dynamic Properties of the Loaded and Unloaded Hemophore HasA: Functional Implications

Wolff

Izadi-Pruneyre

Couprie

et al. 2008

Journal of Molecular Biology

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Section: Conformational and Dynamic Changes Upon Heme Bindingsupporting

confidence: 54%

Comparative Analysis of Structural and Dynamic Properties of the Loaded and Unloaded Hemophore HasA: Functional Implications

Wolff

Izadi-Pruneyre

Couprie

et al. 2008

Journal of Molecular Biology

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“…Similar to what we observe for TTR, other proteins have been already shown to exhibit multiple conformations in solution (Watt et al, 2007;Loria et al, 2008;Rajagoplan et al, 2002;Aparicio et al, 2003). Sometimes, a specific protein conformation is further stabilized by ligand-binding, as is the case for ribonuclease A (Rnase A) and triose phosphate isomerase (TIM) Aparicio et al, 2003;Berlow et al, 2007. Single point mutations may alter protein motions and conformations, changing its affinity for ligands and/or catalysis of enzyme substrates, even if the mutation is not within the active site [reviewed in Loria et al (2008)].…”

Section: Discussionsupporting

confidence: 86%

Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: Implications to tetramer stability and ligand-binding

Trivella

Bleicher

Palmieri

et al. 2010

Journal of Structural Biology

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Transthyretin (TTR) is a tetrameric beta-sheet-rich transporter protein directly involved in human amyloid diseases. It was recently found that the isoflavone genistein (GEN) potently inhibits TTR amyloid fibril formation (Green et al., 2005) and is therefore a promising candidate for TTR amyloidosis treatment. Here we used structural and biophysical approaches to characterize genistein binding to the wild type (TTRwt) and to its most frequent amyloidogenic variant, the V30M mutant. In a dose-dependent manner, genistein elicited considerable increases in both mutant and TTRwt stability as demonstrated by high hydrostatic pressure (HHP) and acid-mediated dissociation/denaturation assays. TTR:GEN crystal complexes and isothermal titration calorimetry (ITC) experiments showed that the binding mechanisms of genistein to the TTRwt and to V30M are different and are dependent on apoTTR structure conformations. Furthermore, we could also identify potential allosteric movements caused by genistein binding to the wild type TTR that explains, at least in part, the frequently observed negatively cooperative process between the two sites of TTRwt when binding ligands. These findings show that TTR mutants may present different ligand recognition and therefore are of value in ligand design for inhibiting TTR amyloidosis.

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“…Now that there is such a large collection of deposited TIM structures (Table 1), it is apparent that the binding process is a twostep process. For example, a structure (1R2R) is known from rabbit TIM in which the loop-6 is closed, but the structure is unliganded [117], while in a trypanosomal TIM structure [118] (1TSI) as well as in a malaria TIM structure (1LZO) [119], loop-6 is seen in an open conformation, while the ligand is still present. The latter structure can also be referred to as an encounter complex, in which the ligand is bound but not yet having completely reached its competent position.…”

Section: The Classical and The Criss-cross Reaction Mechanismmentioning

confidence: 99%

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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Closed Conformation of the Active Site Loop of Rabbit Muscle Triosephosphate Isomerase in the Absence of Substrate: Evidence of Conformational Heterogeneity

Cited by 46 publications

References 80 publications

Comparative Analysis of Structural and Dynamic Properties of the Loaded and Unloaded Hemophore HasA: Functional Implications

Comparative Analysis of Structural and Dynamic Properties of the Loaded and Unloaded Hemophore HasA: Functional Implications

Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: Implications to tetramer stability and ligand-binding

Triosephosphate isomerase: a highly evolved biocatalyst

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