2I8C

Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies

Summary for 2I8C

• Entry DOI: 10.2210/pdb2i8c/pdb
• Related: 2I80 2I87
• Descriptor: D-alanine-D-alanine ligase, SULFATE ION, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: d-alanine:d-alanine ligase, adp complex, staphylococcus aureus, lyase
• Biological source: Staphylococcus aureus subsp. aureus
• Cellular location: Cytoplasm (By similarity): Q5HEB7
• Total number of polymer chains: 2
• Total formula weight: 83768.01

Authors

Liu, S.,Chang, J.S.,Herberg, J.T.,Horng, M.,Tomich, P.K.,Lin, A.H.,Marotti, K.R. (deposition date: 2006-09-01, release date: 2006-09-26, Last modification date: 2023-08-30)

Primary citation

Liu, S.,Chang, J.S.,Herberg, J.T.,Horng, M.M.,Tomich, P.K.,Lin, A.H.,Marotti, K.R.
Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies.
Proc.Natl.Acad.Sci.Usa, 103:15178-15183, 2006

PubMed Abstract: D-alanine:D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. It catalyzes the formation of D-alanine:D-alanine dipeptide, sequentially by using one D-alanine and one ATP as substrates for the first-half reaction, and a second D-alanine substrate to complete the reaction. Some gain of function DDl mutants can use an alternate second substrate, causing resistance to vancomycin, one of the last lines of defense against life-threatening Gram-positive infections. Here, we report the crystal structure of Staphylococcus aureus DDl (StaDDl) and its cocrystal structures with 3-chloro-2,2-dimethyl-N-[4(trifluoromethyl)phenyl]propanamide (inhibitor 1) (Ki=4 microM against StaDDl) and with ADP, one of the reaction products, at resolutions of 2.0, 2.2, and 2.6 A, respectively. The overall structure of StaDDl can be divided into three distinct domains. The inhibitor binds to a hydrophobic pocket at the interface of the first and the third domain. This inhibitor-binding pocket is adjacent to the first D-alanine substrate site but does not overlap with any substrate sites. An allosteric inhibition mechanism of StaDDl by this compound was proposed. The mechanism provides the basis for developing new antibiotics targeting D-alanine:D-alanine ligase. Because this compound only interacts with residues from the first D-alanine site, inhibitors with this binding mode potentially could overcome vancomycin resistance.

PubMed: 17015835
DOI: 10.1073/pnas.0604905103

Experimental method

X-RAY DIFFRACTION (2.46 Å)