5KGN

1.95A resolution structure of independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (2d)

5KGN の概要

• エントリーDOI: 10.2210/pdb5kgn/pdb
• 関連するPDBエントリー: 5KGL 5KGM
• 分子名称: 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, macrocyclic peptide inhibitor, CHLORIDE ION, ... (8 entities in total)
• 機能のキーワード: metal binding, coupled enzyme assay, hts, structure activity relationship, rapid systems, high throughput enzymology, isomerase
• 由来する生物種: Caenorhabditis elegans; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 120870.56

構造登録者

Lovell, S.,Mehzabeen, N.,Battaile, K.P.,Yu, H.,Dranchak, P.,MacArthur, R.,Li, Z.,Carlow, T.,Suga, H.,Inglese, J. (登録日: 2016-06-13, 公開日: 2017-04-05, 最終更新日: 2024-11-06)

主引用文献

Yu, H.,Dranchak, P.,Li, Z.,MacArthur, R.,Munson, M.S.,Mehzabeen, N.,Baird, N.J.,Battalie, K.P.,Ross, D.,Lovell, S.,Carlow, C.K.,Suga, H.,Inglese, J.
Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases.
Nat Commun, 8:14932-14932, 2017

PubMed Abstract: Glycolytic interconversion of phosphoglycerate isomers is catalysed in numerous pathogenic microorganisms by a cofactor-independent mutase (iPGM) structurally distinct from the mammalian cofactor-dependent (dPGM) isozyme. The iPGM active site dynamically assembles through substrate-triggered movement of phosphatase and transferase domains creating a solvent inaccessible cavity. Here we identify alternate ligand binding regions using nematode iPGM to select and enrich lariat-like ligands from an mRNA-display macrocyclic peptide library containing >10 members. Functional analysis of the ligands, named ipglycermides, demonstrates sub-nanomolar inhibition of iPGM with complete selectivity over dPGM. The crystal structure of an iPGM macrocyclic peptide complex illuminated an allosteric, locked-open inhibition mechanism placing the cyclic peptide at the bi-domain interface. This binding mode aligns the pendant lariat cysteine thiolate for coordination with the iPGM transition metal ion cluster. The extended charged, hydrophilic binding surface interaction rationalizes the persistent challenges these enzymes have presented to small-molecule screening efforts highlighting the important roles of macrocyclic peptides in expanding chemical diversity for ligand discovery.

PubMed: 28368002
DOI: 10.1038/ncomms14932

実験手法

X-RAY DIFFRACTION (1.95 Å)