التفاصيل البيبلوغرافية
| العنوان: |
Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. |
| المساهمون: |
Martinez, Juliana A (authoraut), Xiao, Qing (authoraut), Zakarian, Armen (authoraut), Miller, Brian G (authoraut) |
| سنة النشر: |
2017 |
| المجموعة: |
Florida State University: DigiNole Commons |
| مصطلحات موضوعية: |
Adaptor Proteins, Signal Transducing/antagonists & inhibitors, Signal Transducing/chemistry, Signal Transducing/metabolism, Dose-Response Relationship, Drug, Glucokinase/antagonists & inhibitors, Glucokinase/metabolism, Humans, Hypoglycemic Agents/chemistry, Hypoglycemic Agents/pharmacology, Ligands, Models, Molecular, Molecular Structure, Protein Binding/drug effects, Recombinant Proteins/chemistry, Recombinant Proteins/metabolism, Structure-Activity Relationship |
| الوصف: |
The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK-GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK-GKRP interaction. We demonstrate that a small-molecule disruptor of the protein-protein interaction utilizes a two-step conformational selection mechanism to associate with a rare GKRP conformation constituting 3% of the total population. Conformational heterogeneity of GKRP is localized to the N-terminus and deleting this region eliminates the ability of sorbitol 6-phosphate to promote the GCK-GKRP interaction. Stabilizing ligands favor an extended N-terminus, which sterically positions two arginine residues for optimal Coulombic interaction with a pair of carboxylate side chains from GCK. Conversely, disruptors promote a more compact N-terminus in which an interfacial arginine residue is stabilized in an unproductive orientation through a cation-π interaction with tyrosine 75. Eliminating the ability to sample this binding impaired conformation enhances the intrinsic inhibitory activity of GKRP. Elucidating the molecular basis of ligand-mediated control over the GCK-GKRP interaction is expected to impact the development and future refinement of therapeutic agents for diabetes and cardiovascular disease, which result from improper GKRP regulation of GCK. ; Grant Number: R01 DK081358, R01 GM077379, R01 GM115388 ; Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831357. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
1 online resource; computer |
| اللغة: |
English |
| Relation: |
Biochemistry--1520-4995--1520-4995; fsu:641078; (IID) FSU_pmch_28516783; (DOI) 10.1021/acs.biochem.7b00377; (PMCID) PMC5831357; (RID) 28516783; (EID) 28516783; https://diginole.lib.fsu.edu/islandora/object/fsu%3A641078/datastream/TN/view/Antidiabetic%20Disruptors%20of%20the%20Glucokinase-Glucokinase%20Regulatory%20Protein%20Complex%20Reorganize%20a%20Coulombic%20Interface.jpg |
| الاتاحة: |
https://diginole.lib.fsu.edu/islandora/object/fsu%3A641078/datastream/TN/view/Antidiabetic%20Disruptors%20of%20the%20Glucokinase-Glucokinase%20Regulatory%20Protein%20Complex%20Reorganize%20a%20Coulombic%20Interface.jpg |
| رقم الانضمام: |
edsbas.E6D174EA |
| قاعدة البيانات: |
BASE |
