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Dynamics of ligand rebinding to unfolded MbCO by guanidine HCl.

ABSTRACT: Femtosecond vibrational spectroscopy was used to probe a functionally important dynamics and residual structure of myoglobin unfolded by 4 M guanidine HCl. The spectra of the dissociated CO indicated that the residual structure of unfolded myoglobin (Mb) forms a few hydrophobic cavities that could accommodate the dissociated ligand. Geminate rebinding (GR) of CO to the unfolded Mb is three-orders-of-magnitude faster and more efficient than the native Mb but similar to a model heme in a viscous solvent, suggesting that the GR of CO to heme is accelerated by the longer retention of the dissociated ligand near the Fe atom by the poorly-structured protein matrix of the unfolded Mb or viscous solvent. The inefficient GR of CO in native Mb, while dissociated CO is trapped in the primary heme pocket located near the active binding site, indicates that the tertiary structure of the pocket in native Mb plays a functionally significant role.

SUBMITTER: Park J

PROVIDER: S-EPMC2480693 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Dynamics of ligand rebinding to unfolded MbCO by guanidine HCl.

Park Jaeheung J Kim Jooyoung J Lee Taegon T Lim Manho M

Biophysical journal 20080321 11

Femtosecond vibrational spectroscopy was used to probe a functionally important dynamics and residual structure of myoglobin unfolded by 4 M guanidine HCl. The spectra of the dissociated CO indicated that the residual structure of unfolded myoglobin (Mb) forms a few hydrophobic cavities that could accommodate the dissociated ligand. Geminate rebinding (GR) of CO to the unfolded Mb is three-orders-of-magnitude faster and more efficient than the native Mb but similar to a model heme in a viscous s ...[more]

PMID: 18359796

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Project description:ObjectiveA major obstacle in optimizing the performance of closed-loop automated insulin delivery systems has been the delay in insulin absorption and action that results from the subcutaneous (SC) route of insulin delivery leading to exaggerated postmeal hyperglycemic excursions. We aimed to investigate the effect of Afrezza inhaled insulin with ultrafast-in and -out action profile on improving postprandial blood glucose control during hybrid closed-loop (HCL) treatment in young adults with type 1 diabetes.Research design and methodsWe conducted an inpatient, three-way, randomized crossover standardized meal study to assess the efficacy and safety of Afrezza at a low (AL) and a high (AH) dose as compared with a standard SC rapid-acting insulin (aspart) premeal bolus during Diabetes Assistant (DiAs) HCL treatment. Participants received two sequential meals on three study days, and premeal insulin bolus was determined based on home insulin-to-carbohydrate ratio for each meal (rounded up to the closest available Afrezza cartridge dose for AH and down for AL). The primary efficacy outcome was the peak postprandial plasma glucose (PPG) level calculated by pooling data for up to 4 h after the start of each meal. Secondary outcomes included hyperglycemic, hypoglycemic, and euglycemic venous glucose metrics.ResultsThe mean ± SD PPG for the rapid-acting insulin control arm and AH was similar (185 ± 50 mg/dL vs. 195 ± 46 mg/dL, respectively; P = 0.45), while it was higher for meals using AL (208 ± 54 mg/dL, P = 0.04). The AH achieved significantly lower early PPG level than the control arm (30 min; P < 0.001), and improvement in PPG waned at later time points (120 and 180 min; P = 0.02) coinciding with the end of Afrezza glucodynamic action.ConclusionsAfrezza (AH) premeal bolus reduced the early glycemic excursion and improved PPG during HCL compared with aspart premeal bolus. The improvement in PPG was not sustained after the end of Afrezza glucodynamic action at 120 min.

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Dynamics of ligand rebinding to unfolded MbCO by guanidine HCl.

Publications

Dynamics of ligand rebinding to unfolded MbCO by guanidine HCl.

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