7AB0

Apo crystal structure of the MerTK kinase domain

Summary for 7AB0

• Entry DOI: 10.2210/pdb7ab0/pdb
• Related: 7AAX 7AAY 7AAZ
• Descriptor: Tyrosine-protein kinase Mer, CHLORIDE ION (3 entities in total)
• Functional Keywords: tyrosine kinase, apo, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34559.02

Authors

Pflug, A.,Schimpl, M.,McCoull, W.,Nissink, J.W.M.,Overman, R.C.,Rawlins, P.B.,Truman, C.,Underwood, E.,Warwicker, J.,Winter-Holt, J. (deposition date: 2020-09-05, release date: 2020-10-28, Last modification date: 2024-01-31)

Primary citation

Pflug, A.,Schimpl, M.,Nissink, J.W.M.,Overman, R.C.,Rawlins, P.B.,Truman, C.,Underwood, E.,Warwicker, J.,Winter-Holt, J.,McCoull, W.
A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.
Biochem.J., 477:4443-4452, 2020

PubMed Abstract: The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here, we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor 'example 172' (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics, we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.

PubMed: 33119085
DOI: 10.1042/BCJ20200735

Experimental method

X-RAY DIFFRACTION (1.74 Å)