Title:	Structural dynamics of 5-lipoxygenase
DNr:	NAISS 2026/4-602
Project Type:	NAISS Small
Principal Investigator:	Tarvi Teder <tarvi.teder@ki.se>
Affiliation:	Karolinska Institutet
Duration:	2026-03-30 – 2027-04-01
Classification:	10601
Homepage:	https://ki.se/mbb/forskning/kemi-ii-jesper-z-haeggstroms-grupp
Keywords:

Abstract

This project will be conducted within the research group of Prof. Jesper Z. Haeggström at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. The project focuses on the structural and mechanistic characterization of 5-lipoxygenase (5-LOX), a key enzyme in leukotriene biosynthesis and a central regulator of pro-inflammatory lipid mediator production. Dysregulated 5-LOX activity is implicated in a wide range of inflammatory diseases, including asthma, allergy, and cardiovascular disorders, making it an important therapeutic target. 5-LOX catalyzes the initial and rate-limiting steps in leukotriene formation, and its activity is tightly controlled by interactions with cofactors, membrane association, and conformational dynamics. Despite recent structural advances, the molecular mechanisms governing 5-LOX activation, stability, and regulation remain incompletely understood, particularly in relation to dynamic conformational states and ligand-induced effects. This project aims to elucidate the structural dynamics and regulatory mechanisms of 5-LOX using an integrated approach combining structural biology, biochemical assays, and molecular dynamics (MD) simulations. High-resolution structural data will be complemented by MD simulations to investigate conformational flexibility, identify regulatory sites, and characterize the effects of mutations and ligand binding on enzyme activity and stability. Given the limited computational allocation, the MD component will focus on system setup, validation, and initial production simulations, including selected apo, ligand-bound, and mutant 5-LOX systems. These simulations will provide mechanistic insights into key regulatory features and enable prioritization of systems for future large-scale studies. By integrating structural and computational approaches, this project will advance our understanding of 5-LOX regulation at the molecular level and provide a framework for the rational development of targeted modulators of leukotriene biosynthesis.