PDBsum entry 4mkt

Hydrolase

PDB id: 4mkt

Contents

Protein chain

608 a.a.

Ligands

28T

1V6

ACY ×2

Metals

_ZN

_YB ×2

Waters ×653

PDB id:

4mkt

Name:

Hydrolase

Title:

Human leukotriene a4 hydrolase in complex with pro-gly-pro analogue and 4-(4-benzylphenyl)thiazol-2-amine

Structure:

Leukotriene a-4 hydrolase. Chain: a. Synonym: lta-4 hydrolase, leukotriene a(4) hydrolase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lta4, lta4h. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.62Å R-factor: 0.158 R-free: 0.193

Authors:

A.Stsiapanava,A.Rinaldo-Matthis,J.Z.Haeggstrom

Key ref:

A.Stsiapanava et al. (2014). Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. Proc Natl Acad Sci U S A, 111, 4227-4232. PubMed id: 24591641 DOI: 10.1073/pnas.1402136111

Date:

05-Sep-13 Release date: 12-Mar-14

Protein chain

P09960  (LKHA4_HUMAN) -  Leukotriene A-4 hydrolase from Homo sapiens

Seq: 611 a.a.

Struc: 608 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.3.2.6 - leukotriene-A4 hydrolase.
• Reaction: leukotriene A4 + H2O = leukotriene B4

leukotriene A4 + H2O (Bound ligand (Het Group name = 1V6) matches with 44.83% similarity) = leukotriene B4

• Cofactor: Zn(2+)
• Enzyme class 3: E.C.3.4.11.4 - tripeptide aminopeptidase.
• Reaction: Release of a N-terminal residue from a tripeptide.
• Cofactor: Zn(2+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.1402136111

Proc Natl Acad Sci U S A 111:4227-4232 (2014)

PubMed id: 24591641

Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor.

A.Stsiapanava, U.Olsson, M.Wan, T.Kleinschmidt, D.Rutishauser, R.A.Zubarev, B.Samuelsson, A.Rinaldo-Matthis, J.Z.Haeggström.

ABSTRACT

Leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc metalloenzyme that catalyzes the committed step in the formation of the proinflammatory mediator LTB4. Recently, the chemotactic tripeptide Pro-Gly-Pro was identified as an endogenous aminopeptidase substrate for LTA4 hydrolase. Here, we determined the crystal structure of LTA4 hydrolase in complex with a Pro-Gly-Pro analog at 1.72 Å. From the structure, which includes the catalytic water, and mass spectrometric analysis of enzymatic hydrolysis products of Pro-Gly-Pro, it could be inferred that LTA4 hydrolase cleaves at the N terminus of the palindromic tripeptide. Furthermore, we designed a small molecule, 4-(4-benzylphenyl)thiazol-2-amine, denoted ARM1, that inhibits LTB4 synthesis in human neutrophils (IC50 of ∼0.5 μM) and conversion of LTA4 into LTB4 by purified LTA4H with a Ki of 2.3 μM. In contrast, 50- to 100-fold higher concentrations of ARM1 did not significantly affect hydrolysis of Pro-Gly-Pro. A 1.62-Å crystal structure of LTA4 hydrolase in a dual complex with ARM1 and the Pro-Gly-Pro analog revealed that ARM1 binds in the hydrophobic pocket that accommodates the ω-end of LTA4, distant from the aminopeptidase active site, thus providing a molecular basis for its inhibitory profile. Hence, ARM1 selectively blocks conversion of LTA4 into LTB4, although sparing the enzyme's anti-inflammatory aminopeptidase activity (i.e., degradation and inactivation of Pro-Gly-Pro). ARM1 represents a new class of LTA4 hydrolase inhibitor that holds promise for improved anti-inflammatory properties.