التفاصيل البيبلوغرافية
| العنوان: |
Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2. |
| المؤلفون: |
Vaughan RM; Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA., Dickson BM; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA., Martin KR; Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA., MacKeigan JP; Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA. |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 03. Date of Electronic Publication: 2023 Dec 03. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity.
Competing Interests: Conflict of interest: JPM has consulting agreements with Merck and scholarly activity with the Translational Genomics Research Institute (a non-profit organization). |
| معلومات مُعتمدة: |
K00 CA245821 United States CA NCI NIH HHS; R21 CA252430 United States CA NCI NIH HHS; R21 CA263133 United States CA NCI NIH HHS; R21 CA270588 United States CA NCI NIH HHS |
| فهرسة مساهمة: |
Keywords: ULK-101; ULK1; ULK2; autophagy; kinase; molecular dynamics; small molecule inhibitor |
| تواريخ الأحداث: |
Date Created: 20231211 Latest Revision: 20231218 |
| رمز التحديث: |
20231218 |
| مُعرف محوري في PubMed: |
PMC10705459 |
| DOI: |
10.1101/2023.12.01.569261 |
| PMID: |
38077086 |
| قاعدة البيانات: |
MEDLINE |
