PDBsum entry 4u6c

Hydrolase

PDB id: 4u6c

Contents

Protein chain

304 a.a.

Ligands

GOL

Q06

Metals

_CO ×2

__K

Waters ×138

References listed in PDB file

Key reference

• Title: Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type i methionine aminopeptidases.
• Authors: T.Arya, R.Reddi, C.Kishor, R.J.Ganji, S.Bhukya, R.Gumpena, S.Mcgowan, M.Drag, A.Addlagatta.
• Ref.: J Med Chem, 2015, 58, 2350-2357. [DOI no: 10.1021/jm501790e]
• PubMed id: 25699713

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.