Crystal Structures of Saccharomyces cerevisiae N-Myristoyltransferase with Bound Myristoyl-CoA and Inhibitors Reveal the Functional Roles of the N-terminal Region

Wu, Jian; Tao, Yong; Zhang, Meilan; Howard, Michael H.; Gutteridge, Steven; Ding, Jianping

doi:10.1074/jbc.m702696200

Cited by 33 publications

(48 citation statements)

References 48 publications

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“…A crystal structure of S. cerevisiae NMT (ScNMT) with substrate analogues of myristoyl-CoA (myrCoA) and peptides bound confirmed these observations [39]. These and subsequent co-crystal structures have given insight into the binding of myr-CoA and peptide substrates as well as chemical transformation [40][41][42]. Structures of myr-CoA and analogues bound to CaNMT and ScNMT, and more recently also L. major and Leishmania donovani NMTs (LmNMT and LdNMT) indicate that myr-CoA binds in a bent "question mark" conformation (Fig.…”

Section: Myristoyl-coa:protein N-myristoyltransferasementioning

confidence: 55%

“…This is likely to be a conformational change associated with release of myristoylated peptide product [45], although exactly which conformational changes occur upon myrCoA binding and after the chemical reaction remains the subject of debate. Initial crystal structures implied that a particular loop was involved in closing over to form part of the peptide binding site [39][40][41] but a more recent study, which included the N terminus of NMT in the structure-a feature that had either been removed or was disordered in previous studies-indicated that regions of the N terminus could be involved instead [42]. However, this study was carried out with non-peptidic inhibitors of NMT, which bind in a slightly different way to peptide substrates.…”

Section: Myristoyl-coa:protein N-myristoyltransferasementioning

confidence: 99%

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Protein myristoylation in health and disease

et al. 2009

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N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.Keywords Post-translational modification . Drug design . Myristoylation . Lipidation . Chemical proteomics Post-translational modification and myristoylationThe proteome is a larger and more dynamic entity than the genome, a result of both increased sequence diversity at the mRNA level due to alternative splicing of genes, and increased chemical and functional complexity at the protein level due to post-translational modification (PTM). This explains to some extent why larger genomes do not necessarily translate into more complex organisms. Posttranslational modification allows the incorporation of chemistries and new molecular functions that cannot be directly encoded by the gene sequence. Myristoylation is the attachment of a 14-carbon saturated fatty acid, myristate, to the N-terminal glycine of a subset of eukaryotic proteins [8,16,17]. Although often referred to as a PTM, it usually occurs co-translationally [18], when fewer than 100 residues have been polymerised by the

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Section: Myristoyl-coa:protein N-myristoyltransferasementioning

confidence: 55%

Section: Myristoyl-coa:protein N-myristoyltransferasementioning

confidence: 99%

Protein myristoylation in health and disease

et al. 2009

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“…Because binding of the peptides does not affect acyl-CoA binding to the N-terminal motif ( 33,53,54 ), compounds that can recognize the C-terminal binding domain of the NMT proteins of invading pathogens seem to be good candidates to specifi cally disrupt myristoylation without impacting acylation of the proteins of the host (28)(29)(30)(31)(32)(34)(35)(36). As examples, the development of Plasmodium falciparum in erythroid cells is blocked by several chemicals inhibiting the P. falciparum NMT enzyme (35)(36)(37)55 ).…”

Section: Discussionmentioning

confidence: 99%

Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

Soupène¹,

Kao²,

Cheng³

et al. 2016

Journal of Lipid Research

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“…To date, several X-ray crystal structures of CaNMT [22,23] and ScNMT [20,21,24] have been determined, which are potential templates for protozoan parasitic NMTs modeling. The homology scores for the CaNMT compared with PfNMT, LmNMT and TbNMT were 43.0, 44.8, and 46.9%, respectively.…”

Section: Homology Models Of Pfnmt Lmnmt and Tbnmtmentioning

confidence: 99%

“…Among them, most published work has been focused on NMT as an antifungal target. The X-ray crystal structures of NMT from Candida albicans (CaNMT) and Saccharomyces cerevisiae (ScNMT) have been determined in the apo form and in the binary or ternary complexes [20][21][22][23][24]. The availability of these crystal structures has provided important insights into the catalytic mechanism of NMT including conformational changes associated with substrate binding, key residues involved in stabilization of intermediates along the reaction pathway, the role of the oxyanion hole in the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

Sheng

Miao

et al. 2009

J Comput Aided Mol Des

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Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.

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Crystal Structures of Saccharomyces cerevisiae N-Myristoyltransferase with Bound Myristoyl-CoA and Inhibitors Reveal the Functional Roles of the N-terminal Region

Cited by 33 publications

References 48 publications

Protein myristoylation in health and disease

Protein myristoylation in health and disease

Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

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