PDBsum entry 4u6c

Hydrolase

PDB id: 4u6c

Contents

Protein chain

304 a.a.

Ligands

GOL

Q06

Metals

_CO ×2

__K

Waters ×138

PDB id:

4u6c

Name:

Hydrolase

Title:

Hsmetap in complex with [(1r)-1-amino-3-cyclopentylpropyl]phosphonic acid

Structure:

Methionine aminopeptidase 1. Chain: a. Fragment: unp residues 81-386. Synonym: metap 1,peptidase m 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: metap1, kiaa0094. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.91Å R-factor: 0.186 R-free: 0.229

Authors:

T.Arya,A.Addlagatta

Key ref:

T.Arya et al. (2015). Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases. J Med Chem, 58, 2350-2357. PubMed id: 25699713 DOI: 10.1021/jm501790e

Date:

28-Jul-14 Release date: 25-Mar-15

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: 10.1021/jm501790e

J Med Chem 58:2350-2357 (2015)

PubMed id: 25699713

Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases.

T.Arya, R.Reddi, C.Kishor, R.J.Ganji, S.Bhukya, R.Gumpena, S.McGowan, M.Drag, A.Addlagatta.

ABSTRACT

The methionine aminopeptidase (MetAP) family is responsible for the cleavage of the initiator methionine from newly synthesized proteins. Currently, there are no small molecule inhibitors that show selectivity toward the bacterial MetAPs compared to the human enzyme. In our current study, we have screened 20 α-aminophosphonate derivatives and identified a molecule (compound 15) that selectively inhibits the S. pneumonia MetAP in low micromolar range but not the human enzyme. Further bioinformatics, biochemical, and structural analyses suggested that phenylalanine (F309) in the human enzyme and methionine (M205) in the S. pneumonia MetAP at the analogous position render them with different susceptibilities against the identified inhibitor. X-ray crystal structures of various inhibitors in complex with wild type and F309M enzyme further established the molecular basis for the inhibitor selectivity.