Instytut Podstawowych Problemów Techniki

Streszczenie:

Prostaglandin reductase 1 (PTGR1) is an NADPH-dependent enzyme critical to eicosanoid metabolism. Its elevated expression in malignant tumors often correlates with poor prognosis due to its role in protecting cells against reactive oxygen species. This study explores the inhibitory potential of licochalcone A, a flavonoid derived from Xinjiang licorice root, on human PTGR1. Using molecular dynamics simulations, we mapped the enzyme's conformational landscape, revealing a low-energy, rigid-body-like movement of the catalytic domain relative to the nucleotide-binding domain that governs PTGR1's transition between open and closed states. Simulations of NADPH-depleted dimer and NADPH-bound monomer highlighted the critical role of intersubunit interactions and coenzyme binding in defining PTGR1's conformational landscape, offering a deeper understanding of its functional adaptability as a holo-homodimer. Covalent docking, informed by prior chemoproteomic cross-linking data, revealed a highly favorable binding pose for licochalcone A at the NADPH-binding site. This pose aligned with a transient noncovalent binding pose inferred from solvent site-guided molecular docking, emphasizing the stereochemical complementarity of the coenzyme-binding site to licochalcone A. Sequence analysis across PTGR1 orthologs in vertebrates and exploration of 3D structures of human NADPH-binding proteins further underscore the potential of the coenzyme-binding site as a scaffold for developing PTGR1-specific inhibitors, positioning licochalcone A as a promising lead compound.

Słowa kluczowe:

Leukotriene B4 dehydrogenase,NADPH-dependent enzyme,Molecular dynamics simulation,Covalent inhibition,Specific target for cancer therapy

Afiliacje autorów:

Streszczenie:

Wheat germ agglutinin (WGA) demonstrates potential as an oral delivery agent owing to its selective binding to carbohydrates and its capacity to traverse biological membranes. In this study, we employed differential scanning calorimetry and molecular dynamics simulations to comprehensively characterize the thermal unfolding process of both the complete lectin and its four isolated domains. Furthermore, we present the nuclear magnetic resonance structures of three domains that were previously lacking experimental structures in their isolated forms. Our results provide a collective understanding of the energetic and structural factors governing the intricate unfolding mechanism of the complete agglutinin, shedding light on the specific role played by each domain in this process. The analysis revealed negligible interdomain cooperativity, highlighting instead significant coupling between dimer dissociation and the unfolding of the more labile domains. By comparing the dominant interactions, we rationalized the stability differences among the domains. Understanding the structural stability of WGA opens avenues for enhanced drug delivery strategies, underscoring its potential as a promising carrier throughout the gastrointestinal environment.

Słowa kluczowe:

homodimer,hydrogen bonding,lectin,multidomain protein,structural stability,thermal unfolding

Afiliacje autorów: