4IU6: Human Methionine Aminopeptidase In Complex With Fz1: Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1

Citation:
Abstract
Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.
PDB ID: 4IU6Download
MMDB ID: 109655
PDB Deposition Date: 2013/1/19
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 4IU6: monomeric; determined by author and by software (PISA)
Molecular Components in 4IU6
Label Count Molecule
Protein (1 molecule)
1
Methionine Aminopeptidase 1(Gene symbol: METAP1)
Molecule annotation
Chemicals (7 molecules)
1
3
2
1
3
1
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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