5NID

Crystal structure of human LTA4H mutant D375N in open conformation (crystal form II)

Summary for 5NID

• Entry DOI: 10.2210/pdb5nid/pdb
• Related: 4DPR 4MS6 5NI2 5NI4 5NI6 5NIA
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION (3 entities in total)
• Functional Keywords: metallopeptidase, epoxide hydrolase, open conformation, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 70257.28

Authors

Stsiapanava, A. (deposition date: 2017-03-23, release date: 2017-08-23, Last modification date: 2024-01-17)

Primary citation

Stsiapanava, A.,Samuelsson, B.,Haeggstrom, J.Z.
Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis.
Proc. Natl. Acad. Sci. U.S.A., 114:9689-9694, 2017

PubMed Abstract: Human leukotriene (LT) A hydrolase/aminopeptidase (LTAH) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA into LTB, a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTAH complexed with LTA, providing the structural underpinnings of the enzyme's unique epoxide hydrolase (EH) activity, involving Zn, Y383, E271, D375, and two catalytic waters. The structures reveal that a single catalytic water is involved in both catalytic activities of LTAH, alternating between epoxide ring opening and peptide bond hydrolysis, assisted by E271 and E296, respectively. Moreover, we have found two conformations of LTAH, uncovering significant domain movements. The resulting structural alterations indicate that LTA entrance into the active site is a dynamic process that includes rearrangement of three moving domains to provide fast and efficient alignment and processing of the substrate. Thus, the movement of one dynamic domain widens the active site entrance, while another domain acts like a lid, opening and closing access to the hydrophobic tunnel, which accommodates the aliphatic tale of LTA during EH reaction. The enzyme-LTA complex structures and dynamic domain movements provide critical insights for development of drugs targeting LTAH.

PubMed: 28827365
DOI: 10.1073/pnas.1710850114

Experimental method

X-RAY DIFFRACTION (1.568 Å)