3V8R

Crystal structure of NAD kinase 1 H223E mutant from Listeria monocytogenes in complex with 5'-amino-8-bromo-5'-deoxyadenosine

Summary for 3V8R

• Entry DOI: 10.2210/pdb3v8r/pdb
• Related: 2I2C 3V7V 3V7W 3V7Y 3V80 3V8M 3V8N 3V8P 3V8Q
• Descriptor: Probable inorganic polyphosphate/ATP-NAD kinase 1, 5'-amino-8-bromo-5'-deoxyadenosine, CITRIC ACID, ... (4 entities in total)
• Functional Keywords: ligand-screening by crystallography, two-domain kinase, inorganic polyphosphate/atp-nad kinase 1, transferase
• Biological source: Listeria monocytogenes
• Total number of polymer chains: 1
• Total formula weight: 31918.67

Authors

Gelin, M.,Poncet-Montange, G.,Assairi, L.,Morellato, L.,Huteau, V.,Dugu, L.,Dussurget, O.,Pochet, S.,Labesse, G. (deposition date: 2011-12-23, release date: 2012-03-14, Last modification date: 2024-02-28)

Primary citation

Gelin, M.,Poncet-Montange, G.,Assairi, L.,Morellato, L.,Huteau, V.,Dugue, L.,Dussurget, O.,Pochet, S.,Labesse, G.
Screening and In Situ Synthesis Using Crystals of a NAD Kinase Lead to a Potent Antistaphylococcal Compound.
Structure, 20:1107-1117, 2012

PubMed Abstract: Making new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro.

PubMed: 22608967
DOI: 10.1016/j.str.2012.03.024

Experimental method

X-RAY DIFFRACTION (2.39 Å)