TY - JOUR
T1 - Screening and in situ synthesis using crystals of a NAD kinase lead to a potent antistaphylococcal compound
AU - Gelin, Muriel
AU - Poncet-Montange, Guillaume
AU - Assairi, Liliane
AU - Morellato, Laurence
AU - Huteau, Valérie
AU - Dugué, Laurence
AU - Dussurget, Olivier
AU - Pochet, Sylvie
AU - Labesse, Gilles
N1 - Funding Information:
We thank Jean-François Guichou, Martin Cohen-Gonsaud, William Bourguet, and Cathy Royer for helpful discussion. We acknowledge corrections of English language in the manuscript by Lucas Black. We also acknowledge the people at the ESRF (Grenoble, France) for the beamlines for biological crystallography, ID14-1, ID14-2, ID14-4, and ID29. We thank Pierre Germain and Geneviève Aubert for cytotoxic assays on HeLa and MRC5 cells, respectively. We acknowledge financial support from the CNRS, INSERM, Institut Pasteur, Institut Curie, and the ANR (Blanc 06-1_137054). M.G. and L.M. were supported by grants from the ANR.
PY - 2012/6/6
Y1 - 2012/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861993424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861993424&partnerID=8YFLogxK
U2 - 10.1016/j.str.2012.03.024
DO - 10.1016/j.str.2012.03.024
M3 - Article
C2 - 22608967
AN - SCOPUS:84861993424
SN - 0969-2126
VL - 20
SP - 1107
EP - 1117
JO - Structure
JF - Structure
IS - 6
ER -