6EU5

Leishmania major N-myristoyltransferase with bound myristoyl-CoA and inhibitor

Summary for 6EU5

• Entry DOI: 10.2210/pdb6eu5/pdb
• Related: 2WSA
• Descriptor: Glycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, 4-[3-[(8~{a}~{R})-3,4,6,7,8,8~{a}-hexahydro-1~{H}-pyrrolo[1,2-a]pyrazin-2-yl]propyl]-2,6-bis(chloranyl)-~{N}-methyl-~{N}-(1,3,5-trimethylpyrazol-4-yl)benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: n-myristoyltransferase, selective inhibitor, parasite, transferase
• Biological source: Leishmania major
• Total number of polymer chains: 1
• Total formula weight: 52005.65

Authors

Brenk, R.,Kehrein, J.,Kersten, C. (deposition date: 2017-10-27, release date: 2019-02-06, Last modification date: 2024-01-17)

Primary citation

Kersten, C.,Fleischer, E.,Kehrein, J.,Borek, C.,Jaenicke, E.,Sotriffer, C.,Brenk, R.
How To Design Selective Ligands for Highly Conserved Binding Sites: A Case Study UsingN-Myristoyltransferases as a Model System.
J.Med.Chem., 2019

PubMed Abstract: A model system of two related enzymes with conserved binding sites, namely -myristoyltransferase from two different organisms, was studied to decipher the driving forces that lead to selective inhibition in such cases. Using a combination of computational and experimental tools, two different selectivity-determining features were identified. For some ligands, a change in side-chain flexibility appears to be responsible for selective inhibition. Remarkably, this was observed for residues orienting their side chains away from the ligands. For other ligands, selectivity is caused by interfering with a water molecule that binds more strongly to the off-target than to the target. On the basis of this finding, a virtual screen for selective compounds was conducted, resulting in three hit compounds with the desired selectivity profile. This study delivers a guideline on how to assess selectivity-determining features in proteins with conserved binding sites and to translate this knowledge into the design of selective inhibitors.

PubMed: 31423787
DOI: 10.1021/acs.jmedchem.9b00586

Experimental method

X-RAY DIFFRACTION (1.49608302465 Å)