PDBsum entry 4hxx

Hydrolase/hydrolase inhibitor

PDB id: 4hxx

Contents

Protein chain

304 a.a.

Ligands

1AY

SO4 ×2

Metals

_CO ×3

__K

Waters ×158

PDB id:

4hxx

Name:

Hydrolase/hydrolase inhibitor

Title:

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1

Structure:

Methionine aminopeptidase 1. Chain: a. Fragment: unp residues 81-384. Synonym: map 1, metap 1, peptidase m 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: bl21. Gene: kiaa0094, metap1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.09Å R-factor: 0.194 R-free: 0.258

Authors:

S.B.Gabelli,F.Zhang,J.Liu,L.M.Amzel

Key ref:

P.Zhang et al. (2013). Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1. Bioorg Med Chem Lett, 21, 2600-2617. PubMed id: 23507151 DOI: 10.1016/j.bmc.2013.02.023

Date:

12-Nov-12 Release date: 03-Apr-13

Protein chain

P53582  (MAP11_HUMAN) -  Methionine aminopeptidase 1 from Homo sapiens

Seq: 386 a.a.

Struc: 304 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.11.18 - methionyl aminopeptidase.
• Reaction: Release of N-terminal amino acids, preferentially methionine, from peptides and arylamides.
• Cofactor: Cobalt cation

DOI no: 10.1016/j.bmc.2013.02.023

Bioorg Med Chem Lett 21:2600-2617 (2013)

PubMed id: 23507151

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.

P.Zhang, X.Yang, F.Zhang, S.B.Gabelli, R.Wang, Y.Zhang, S.Bhat, X.Chen, M.Furlani, L.M.Amzel, J.O.Liu, D.Ma.

ABSTRACT

Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1.