6O5H
The effect of modifier structure on the activation of leukotriene A4 hydrolase aminopeptidase activity.
Summary for 6O5H
| Entry DOI | 10.2210/pdb6o5h/pdb |
| Descriptor | Leukotriene A-4 hydrolase, 4-{4-[(4-methoxyphenyl)methyl]phenyl}-1,3-thiazol-2-amine, ZINC ION, ... (4 entities in total) |
| Functional Keywords | leukotriene a4 hydrolase, 4-ome-arm1, aminipeptidase, activator, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 3 |
| Total formula weight | 208105.03 |
| Authors | Noble, S.M.,Lee, K.H.,Paige, M. (deposition date: 2019-03-03, release date: 2019-12-04, Last modification date: 2024-03-13) |
| Primary citation | Lee, K.H.,Petruncio, G.,Shim, A.,Burdick, M.,Zhang, Z.,Shim, Y.M.,Noble, S.M.,Paige, M. Effect of Modifier Structure on the Activation of Leukotriene A4Hydrolase Aminopeptidase Activity. J.Med.Chem., 62:10605-10616, 2019 Cited by PubMed Abstract: Activation of the leukotriene A hydrolase (LTAH) 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 LTAH with potential anti-inflammatory properties. To investigate the effect of modifier structure on enzyme kinetics of LTAH, 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 LTAH 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 LTB production in human neutrophils. PubMed: 31751136DOI: 10.1021/acs.jmedchem.9b00663 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.84 Å) |
Structure validation
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