5BMM

Src in complex with DNA-templated macrocyclic inhibitor MC25b

Summary for 5BMM

• Entry DOI: 10.2210/pdb5bmm/pdb
• Related PRD ID: PRD_002183
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, macrocyclic inhibitor MC25b (3 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Gallus gallus (Chicken); More
• Cellular location: Cell membrane : P00523
• Total number of polymer chains: 4
• Total formula weight: 66934.84

Authors

Georghiou, G.,Guja, K.E.,Aleem, S.,Kleiner, R.E.,Liu, D.R.,Miller, W.T.,Garcia-Diaz, M.,Seeliger, M.A. (deposition date: 2015-05-22, release date: 2016-09-21, Last modification date: 2023-11-15)

Primary citation

Aleem, S.U.,Georghiou, G.,Kleiner, R.E.,Guja, K.E.,Craddock, B.P.,Lyczek, A.,Chan, A.I.,Garcia-Diaz, M.,Miller, W.T.,Liu, D.R.,Seeliger, M.A.
Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles.
Cell Chem Biol, 23:1103-1112, 2016

PubMed Abstract: Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.

PubMed: 27593110
DOI: 10.1016/j.chembiol.2016.07.017

Experimental method

X-RAY DIFFRACTION (2.5 Å)