PDBsum entry 4cgo

Transferase

PDB id: 4cgo

Contents

Protein chain

411 a.a.

Ligands

MYA

6KV ×2

Metals

_MG

Waters ×575

PDB id:

4cgo

Name:

Transferase

Title:

Leishmania major n-myristoyltransferase in complex with a thienopyrimidine inhibitor

Structure:

Glycylpeptide n-tetradecanoyltransferase. Chain: a. Fragment: residues 11-421. Engineered: yes

Source:

Leishmania major. Organism_taxid: 5664. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss, rosetta2.

Resolution:

1.30Å R-factor: 0.163 R-free: 0.196

Authors:

J.A.Brannigan,S.M.Roberts,A.S.Bell,J.A.Hutton,D.F.Smith,E.W.Tate, R.J.Leatherbarrow,A.J.Wilkinson

Key ref:

J.A.Brannigan et al. (2014). Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors. Iucrj, 1, 250-260. PubMed id: 25075346 DOI: 10.1107/S2052252514013001

Date:

25-Nov-13 Release date: 09-Jul-14

Protein chain

Q4Q5S8  (Q4Q5S8_LEIMA) -  Glycylpeptide N-tetradecanoyltransferase from Leishmania major

Seq: 421 a.a.

Struc: 411 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.1.97 - glycylpeptide N-tetradecanoyltransferase.
• Reaction: N-terminal glycyl-[protein] + tetradecanoyl-CoA = N-tetradecanoylglycyl- [protein] + CoA + H⁺

N-terminal glycyl-[protein] + tetradecanoyl-CoA (Bound ligand (Het Group name = MYA) corresponds exactly) = N-tetradecanoylglycyl- [protein] + CoA + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1107/S2052252514013001

Iucrj 1:250-260 (2014)

PubMed id: 25075346

Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors.

J.A.Brannigan, S.M.Roberts, A.S.Bell, J.A.Hutton, M.R.Hodgkinson, E.W.Tate, R.J.Leatherbarrow, D.F.Smith, A.J.Wilkinson.

ABSTRACT

The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic α-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.