4IKR

Crystal structure of Type 1 human methionine aminopeptidase in complex with 2-(4-(5-chloro-6-methyl-2-(pyridin-2-yl)pyrimidin-4-yl)piperazin-1-yl)ethanol

Summary for 4IKR

• Entry DOI: 10.2210/pdb4ikr/pdb
• Related: 2NQ7 4IKS 4IKT 4IKU
• Descriptor: Methionine aminopeptidase 1, COBALT (II) ION, 2-{4-[5-chloro-6-methyl-2-(pyridin-2-yl)pyrimidin-4-yl]piperazin-1-yl}ethanol, ... (6 entities in total)
• Functional Keywords: pita-bread fold, aminopeptidase, ribosome, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37577.73

Authors

Addlagatta, A.,Kishor, C.,Arya, T. (deposition date: 2012-12-28, release date: 2013-12-11, Last modification date: 2024-03-20)

Primary citation

Kishor, C.,Arya, T.,Reddi, R.,Chen, X.,Saddanapu, V.,Marapaka, A.K.,Gumpena, R.,Ma, D.,Liu, J.O.,Addlagatta, A.
Identification, Biochemical and Structural Evaluation of Species-Specific Inhibitors against Type I Methionine Aminopeptidases
J.Med.Chem., 56:5295-5305, 2013

PubMed Abstract: Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.

PubMed: 23767698
DOI: 10.1021/jm400395p

Experimental method

X-RAY DIFFRACTION (1.78 Å)