Characterizing global substates of myoglobin

Andrews, Brian; Romo, Tod D.; Clarage, James; Pettitt, B. Montgomery; Phillips, George N.

doi:10.1016/s0969-2126(98)00060-4

Cited by 43 publications

(46 citation statements)

References 35 publications

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“…Dynamics of hbLBD-Proteins are known to be dynamic, and they sample numerous conformational states (67,68). The concept of a free energy landscape suggests that even the so-called native state of a protein is actually a statistical ensemble of different conformational substrates with similar free energies (69).…”

Section: Discussionmentioning

confidence: 99%

Solution Structure and Dynamics of the Lipoic Acid-bearing Domain of Human Mitochondrial Branched-chain α-Keto Acid Dehydrogenase Complex

Chang

Chou

Chuang

et al. 2002

Journal of Biological Chemistry

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The lipoyl-bearing domain (LBD) of the transacylase (E2) subunit of the branched-chain ␣-keto acid dehydrogenase complex plays a central role in substrate channeling in this mitochondrial multienzyme complex. We have employed multidimensional heteronuclear NMR techniques to determine the structure and dynamics of the LBD of the human branched-chain ␣-keto acid dehydrogenase complex (hbLBD). Similar to LBD from other members of the ␣-keto acid dehydrogenase family, the solution structure of hbLBD is a flattened ␤-barrel formed by two four-stranded antiparallel ␤-sheets. The lipoyl Lys 44 residue resides at the tip of a ␤-hairpin comprising a sharp type I ␤-turn and the two connecting ␤-strands 4 and 5. A prominent V-shaped groove formed by a surface loop, L1, connecting ␤1-and ␤2-strands and the lipoyl lysine ␤-hairpin constitutes the functional pocket. We further applied reduced spectral density functions formalism to extract dynamic information of hbLBD from 15 N-T 1 , 15 N-T 2 , and ( 1 H-15 N) nuclear Overhauser effect data obtained at 600 MHz. The results showed that residues surrounding the lipoyl lysine region comprising the L1 loop and the Lys 44 ␤-turn are highly flexible, whereas ␤-sheet S1 appears to display a slow conformational exchange process.The mammalian mitochondrial branched-chain ␣-keto acid dehydrogenase (BCKD) 1 complex catalyzes the oxidative decarboxylation of branched-chain ␣-keto acids derived from leucine, isoleucine, and valine to give rise to branched-chain acyl-CoAs (1). The reaction products are indirectly channeled into the Krebs cycle or linked to lipid and cholesterol biosynthesis. In patients with inherited maple syrup urine disease, the activity of the BCKD complex is deficient, which results in the accumulation of branched-chain ␣-keto acids. This metabolic block has severe clinical consequences including often fatal ketoacidosis, neurological derangement, and mental retardation in survivors (2).The mammalian BCKD complex is a member of the highly conserved ␣-keto acid dehydrogenase complexes consisting of the pyruvate dehydrogenase complex (PDC), the ␣-ketoglutarate dehydrogenase complex (KGDC), and the BCKD complex with similar structure and function (3). The mammalian BCKD complex consists of three catalytic components as follows: a heterotetrameric (␣ 2 ␤ 2 ) branched-chain ␣-keto acid decarboxylase or E1, a homo-24-meric dihydrolipoyltransacylase or E2, and a homodimeric dihydrolipoamide dehydrogenase or E3. E1 and E2 components are specific for the BCKD complex, whereas the E3 component is common among the three ␣-keto acid dehydrogenase complexes. In addition, the mammalian BCKD complex contains two regulatory enzymes, the BCKD kinase and the BCKD phosphatase that regulate activity of the BCKD complex through phosphorylation (inactivation)/dephosphorylation (activation) cycles (4). The BCKD complex is organized around the cubic E2 core, to which 12 copies of E1, and unspecified copies of E3, the BCKD kinase, and the BCKD phosphatase are attached through ionic interact...

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Section: Discussionmentioning

confidence: 99%

Solution Structure and Dynamics of the Lipoic Acid-bearing Domain of Human Mitochondrial Branched-chain α-Keto Acid Dehydrogenase Complex

Chang

Chou

Chuang

et al. 2002

Journal of Biological Chemistry

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show abstract

“…In fact, the structures of the configurational space of Mb arise from the regular arrangement of relatively rigid a-helices [25]. Moreover, it was observed that even minute changes in the dynamical properties of the system alter the configurational space projection [25]. Therefore, we assigned to the same cluster those conformations that share most of their secondary structure motifs, i.e.…”

Section: Identification Of Representative Structures In the Trajectoriesmentioning

confidence: 99%

Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: The myoglobin case

Papaleo

Mereghetti

Fantucci

et al. 2009

Journal of Molecular Graphics and Modelling

346

224

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“…To solve that calculates distances between each node of the der identical conditions. The myoglobin simulation is regrid and each solute atom would be prohibitively ported in a separate paper, 31 and therefore, only a brief…”

Section: Distribution Functionsmentioning

confidence: 99%