The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase

Gajiwala, Ketan S.; Grodsky, Neil; Bolaños, Ben; Feng, Junli; Ferre, RoseAnn; Timofeevski, Sergei; Xu, Meirong; Murray, Brion W.; Johnson, Ted W.; Stewart, Al

doi:10.1074/jbc.m116.771485

Title: The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase

Journal Article · Wed Jul 19 00:00:00 UTC 2017 · Journal of Biological Chemistry

DOI: https://doi.org/10.1074/jbc.m116.771485 · OSTI ID:1405020

Gajiwala, Ketan S. ^[1]; Grodsky, Neil ^[1]; Bolaños, Ben ^[1]; Feng, Junli ^[1]; Ferre, RoseAnn ^[1]; Timofeevski, Sergei ^[2]; Xu, Meirong ^[2]; Murray, Brion W. ^[2]; Johnson, Ted W. ^[1]; Stewart, Al ^[1]

Pfizer Worldwide Research and Development, San Diego, CA (United States). Oncology Medicinal Chemistry
Pfizer Worldwide Research and Development, San Diego, CA (United States). Oncology Research and Development

The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1405020

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 38 Vol. 292; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
enzyme inhibitor
protein dynamic
protein kinase
protein stability
protein structure

Title: The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase

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