6Y81

Fragment KCL_1088 in complex with MAP kinase p38-alpha

Summary for 6Y81

• Entry DOI: 10.2210/pdb6y81/pdb
• Descriptor: Mitogen-activated protein kinase 14, 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE, CALCIUM ION, ... (8 entities in total)
• Functional Keywords: fbdd, fragment based drug design, p38, mapk14, kinase, transferase
• Biological source: Mus musculus (House mouse)
• Total number of polymer chains: 1
• Total formula weight: 42677.74

Authors

De Nicola, G.F.,Nichols, C.E. (deposition date: 2020-03-03, release date: 2020-03-11, Last modification date: 2024-01-24)

Primary citation

Nichols, C.,Ng, J.,Keshu, A.,Kelly, G.,Conte, M.R.,Marber, M.S.,Fraternali, F.,De Nicola, G.F.
Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1 beta-IL1R and p38 alpha-TAB1 Complexes.
J.Med.Chem., 63:7559-7568, 2020

PubMed Abstract: Nowadays, it is possible to combine X-ray crystallography and fragment screening in a medium throughput fashion to chemically probe the surfaces used by proteins to interact and use the outcome of the screens to systematically design protein-protein inhibitors. To prove it, we first performed a bioinformatics analysis of the Protein Data Bank protein complexes, which revealed over 400 cases where the crystal lattice of the target in the free form is such that large portions of the interacting surfaces are free from lattice contacts and therefore accessible to fragments during soaks. Among the tractable complexes identified, we then performed single fragment crystal screens on two particular interesting cases: the Il1β-ILR and p38α-TAB1 complexes. The result of the screens showed that fragments tend to bind in clusters, highlighting the small-molecule hotspots on the surface of the target protein. In most of the cases, the hotspots overlapped with the binding sites of the interacting proteins.

PubMed: 32543856
DOI: 10.1021/acs.jmedchem.0c00403

Experimental method

X-RAY DIFFRACTION (1.54 Å)