Crystal Structures of Leishmania mexicana Phosphoglycerate Mutase Suggest a One-Metal Mechanism and a New Enzyme Subclass

Nowicki, Matthew W.; Kuaprasert, Buabarn; McNae, I.W.; Morgan, Hugh P.; Harding, Marjorie M.; Michels, Paul A.M.; Fothergill‐Gilmore, Linda A.; Walkinshaw, Malcolm D.

doi:10.1016/j.jmb.2009.09.041

Cited by 24 publications

(19 citation statements)

References 58 publications

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“…X-ray crystal structures have been obtained for the enzymes derived from two trypanosomatids and several bacterial species8252627.…”

Section: Resultsmentioning

confidence: 99%

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Dranchak

et al. 2017

Nat Commun

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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 >1012 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.

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“…X-ray crystal structures have been obtained for the enzymes derived from two trypanosomatids and several bacterial species8252627.…”

Section: Resultsmentioning

confidence: 99%

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Dranchak

et al. 2017

Nat Commun

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“…Moreover, rational design of inhibitors based on molecular target structures has not yet proved feasible. iPGAM structures for the tropical parasite Leishmania mexicana [11] and various Bacillus species [3,6,12] co‐crystallized with their natural substrates 3PGA/2PGA have been reported. When the active site is occupied by the substrate, the ligand is buried and is therefore inaccessible to the solvent.…”

Section: Introductionmentioning

confidence: 99%

Structural role of the active‐site metal in the conformation of Trypanosoma brucei phosphoglycerate mutase

et al. 2012

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Phosphoglycerate mutases (PGAMs) participate in both the glycolytic and the gluconeogenic pathways in reversible isomerization of 3-phosphoglycerate and 2-phosphoglycerate. PGAMs are members of two distinct protein families: enzymes that are dependent on or independent of the 2,3-bisphosphoglycerate cofactor. We determined the X-ray structure of the monomeric Trypanosoma brucei independent PGAM (TbiPGAM) in its apoenzyme form, and confirmed this observation by small angle X-ray scattering data. Comparing the TbiPGAM structure with the Leishmania mexicana independent PGAM structure, previously reported with a phosphoglycerate molecule bound to the active site, revealed the domain movement resulting from active site occupation. The structure reported here shows the interaction between Asp319 and the metal bound to the active site, and its contribution to the domain movement. Substitution of the metal-binding residue Asp319 by Ala resulted in complete loss of independent PGAM activity, and showed for the first time its involvement in the enzyme's function. As TbiPGAM is an attractive molecular target for drug development, the apoenzyme conformation described here provides opportunities for its use in structure-based drug design approaches. DatabaseStructural data for the Trypanosoma brucei 2,3-bisphosphoglycerate-independent phosphoglycerate mutase (iPGAM) has been deposited with the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank under code 3NVL. Structured digital abstractl TbiPGAM and TbiPGAM bind by x-ray crystallography (View interaction)

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“…Oxoacyl acyl-carrier-protein reductase (OAR) 2C07 [198] Peptide deformylase (PDF) 1JYM [199]; 1RL4, 1RQC [200] Peroxisomal targeting signal 1 (PTS1) 3CV0, 3CVL, CVN, 3CVP, 3CVQ [201] Peroxisomal targeting signal 2 (PTS2) 2F2J [110] Phosphethanolamine methyltransferase (PMT) 3UJ6, 3UJ7, 3UJ8, 3UJ9, 3UJA, 3UJB [202] Phosphodiesterase B1 (PDEB1) 2R8Q [203] 4I15 [204] Phosphodiesterase C (PDEC) 3V93 [205]; 3V94 [206] Phosphoenolpyruvate carboxykinase (PEPCH) 1II2 [207] Phosphofructokinase (PFK) 3F5M [208] 6-Phosphoglucolactonase (6PGL) 2J0E [209]; 3E7F, 3EB9 [210] 6-Phosphogluconate dehydrogenase (6PGDH) 1PGJ [211] Phosphoglucose isomerase (PGI) 1Q50, 1T10 [212] 2O2C, 2O2D [213] Phosphoglycerate kinase (PGK) 3OZA, 3OZ7 [214] 13PK [215]; 16PK [216] Phosphoglycerate mutase (PGAM) 3IGY, 3IGZ [217] 3EOZ [218] 3NVL [219] [220] 3F9R [221] Plasmepsin I (PMI) 2R9B [222]; 3QRV, 3QS1 [223];…”

Section: Brucei T Cruzimentioning

confidence: 99%

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Ogungbe

Setzer

2016

Molecules

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Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.

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Crystal Structures of Leishmania mexicana Phosphoglycerate Mutase Suggest a One-Metal Mechanism and a New Enzyme Subclass

Cited by 24 publications

References 58 publications

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Structural role of the active‐site metal in the conformation of Trypanosoma brucei phosphoglycerate mutase

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

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