PDBsum entry 6o5h

Hydrolase

PDB id: 6o5h

Contents

Protein chains

607 a.a.

Ligands

LNJ ×3

Metals

_ZN ×3

Waters ×356

References listed in PDB file

Key reference

• Title: Effect of modifier structure on the activation of leukotriene a₄ hydrolase aminopeptidase activity.
• Authors: K.H.Lee, G.Petruncio, A.Shim, M.Burdick, Z.Zhang, Y.M.Shim, S.M.Noble, M.Paige.
• Ref.: J Med Chem, 2019, 62, 10605-10616. [DOI no: 10.1021/acs.jmedchem.9b00663]
• PubMed id: 31751136

Abstract

Activation of the leukotriene A₄ hydrolase (LTA₄H) aminopeptidase (AP) activity with 4-methoxydiphenylmethane (4MDM) promoted resolution of neutrophil infiltration in a murine cigarette smoke-induced model for emphysematous chronic obstructive pulmonary disease. Recently, 4-(4-benzylphenyl)thiazol-2-amine (ARM1) was published as a ligand for LTA₄H with potential anti-inflammatory properties. To investigate the effect of modifier structure on enzyme kinetics of LTA₄H, a series of analogues bearing structural features of ARM1 and 4MDM were synthesized using trifluoroborate Suzuki coupling reactions. Following, the 2.8 Å X-ray crystal structure of LTA₄H complexed with 4-OMe-ARM1, a 4MDM-ARM1 hybrid molecule, was determined. Kinetic analysis showed that ARM1 and related analogues lowered affinity for the enzyme-substrate complex, resulting in a change of mechanism from hyperbolic mixed predominately catalytic activation (HMx(Sp < Ca)A) as observed for 4MDM to a predominately specific activation (HMx(Sp > Ca)A) mechanism. 4-OMe-ARM1 was then shown to dose responsively reduce LTB₄ production in human neutrophils.