6K26

Crystal structure of Vibrio cholerae methionine aminopeptidase

Summary for 6K26

• Entry DOI: 10.2210/pdb6k26/pdb
• Descriptor: Methionine aminopeptidase, SODIUM ION (3 entities in total)
• Functional Keywords: hydrolase, metap, methionine aminopeptidase
• Biological source: Vibrio cholerae
• Total number of polymer chains: 2
• Total formula weight: 66930.29

Authors

Pillalamarri, V.,Addlagatta, A. (deposition date: 2019-05-13, release date: 2020-05-20, Last modification date: 2023-11-22)

Primary citation

Pillalamarri, V.,Reddy, C.G.,Bala, S.C.,Jangam, A.,Kutty, V.V.,Addlagatta, A.
Methionine aminopeptidases with short sequence inserts within the catalytic domain are differentially inhibited: Structural and biochemical studies of three proteins from Vibrio spp.
Eur.J.Med.Chem., 209:112883-112883, 2020

PubMed Abstract: Methionine aminopeptidases (MetAPs) have been recognized as drug targets and have been extensively studied for discovery of selective inhibitors. MetAPs are essential enzymes in all living cells. While most prokaryotes contain a single gene, some prokaryotes and all eukaryotes including human have redundancy. Due to the similarity in the active sites of the MetAP enzyme between the pathogens and human limited the success of discovering selective inhibitors. We recently have discovered that MetAPs with small inserts within the catalytic domain to have different susceptibilities against some inhibitors compared to those that do not have. Using this clue we used bioinformatic tools to identify new variants of MetAPs with inserts in pathogenic species. Two new isoforms were identified in Vibrio species with two and three inserts in addition to an isoform without any insert. Multiple sequence alignment suggested that inserts are conserved in several of the Vibrio species. Two of the three inserts are common between two and three insert isoforms. One of the inserts is identified to have "NNKNN" motif that is similar to well-characterized quorum sensing peptide, "NNWNN". Another insert is predicted to have a posttranslational modification site. Three Vibrio proteins were cloned, expressed, purified, enzyme kinetics established and inhibitor screening has been performed. Several of the pyridinylpyrimidine derivatives selectively inhibited MetAPs with inserts compared to those that do not have, including the human enzyme. Crystal structure and molecular modeling studies provide the molecular basis for selective inhibition.

PubMed: 33035924
DOI: 10.1016/j.ejmech.2020.112883

Experimental method

X-RAY DIFFRACTION (1.85 Å)