5O0B

Crystal structure of Phosphopantetheine adenylyltransferase from Mycobacterium abcessus in complex with 3-Bromo-1H-indazole-5-carboxylic acid (Fragment 2)

Summary for 5O0B

• Entry DOI: 10.2210/pdb5o0b/pdb
• Descriptor: Phosphopantetheine adenylyltransferase, 3-bromanyl-1~{H}-indazole-5-carboxylic acid (3 entities in total)
• Functional Keywords: coenzyme a biosynthesis, transferase
• Biological source: Mycobacterium abscessus (strain ATCC 19977 / DSM 44196 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543)
• Cellular location: Cytoplasm : B1MDL6
• Total number of polymer chains: 3
• Total formula weight: 53876.91

Authors

Thomas, S.E.,Kim, S.Y.,Mendes, V.,Blaszczyk, M.,Blundell, T.L. (deposition date: 2017-05-16, release date: 2017-06-28, Last modification date: 2024-01-17)

Primary citation

Thomas, S.E.,Mendes, V.,Kim, S.Y.,Malhotra, S.,Ochoa-Montano, B.,Blaszczyk, M.,Blundell, T.L.
Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections: A Paper Dedicated to John Kendrew.
J. Mol. Biol., 429:2677-2693, 2017

PubMed Abstract: Interest in applications of protein crystallography to medicine was evident, as the first high-resolution structures emerged in the 50s and 60s. In Cambridge, Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to hemoglobin, while in Oxford, the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign, as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimization of interactions of hits using the structure of the target protein. Early examples of this approach were the use of the structure of renin to design antihypertensives and the structure of HIV protease in design of AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design and has been used to progress three oncology drugs through clinical trials to FDA approval. We exemplify current developments in structure-guided target identification and fragment-based lead discovery with efforts to develop new antimicrobials for mycobacterial infections.

PubMed: 28648615
DOI: 10.1016/j.jmb.2017.06.014

Experimental method

X-RAY DIFFRACTION (1.735 Å)