An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1

Yohendran Baskaran, Khay C. Ang, Praju V. Anekal, Wee L. Chan, Jonathan M. Grimes, Ed Manser, Robert C. Robinson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

PAK4 is a metazoan-specific kinase acting downstream of Cdc42. Here we describe the structure of human PAK4 in complex with Inka1, a potent endogenous kinase inhibitor. Using single mammalian cells containing crystals 50 μm in length, we have determined the in cellulo crystal structure at 2.95 Å resolution, which reveals the details of how the PAK4 catalytic domain binds cellular ATP and the Inka1 inhibitor. The crystal lattice consists only of PAK4-PAK4 contacts, which form a hexagonal array with channels of 80 Å in diameter that run the length of the crystal. The crystal accommodates a variety of other proteins when fused to the kinase inhibitor. Inka1-GFP was used to monitor the process crystal formation in living cells. Similar derivatives of Inka1 will allow us to study the effects of PAK4 inhibition in cells and model organisms, to allow better validation of therapeutic agents targeting PAK4.

Original languageEnglish
Article number8681
JournalNature communications
Volume6
DOIs
Publication statusPublished - Nov 26 2015
Externally publishedYes

Fingerprint

inhibitors
Phosphotransferases
Crystals
crystals
Cells
adenosine triphosphate
Catalytic Domain
Adenosine Triphosphate
organisms
crystal lattices
Crystal lattices
Crystal structure
Derivatives
proteins
crystal structure
Proteins
cells
Therapeutics

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Baskaran, Y., Ang, K. C., Anekal, P. V., Chan, W. L., Grimes, J. M., Manser, E., & Robinson, R. C. (2015). An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Nature communications, 6, [8681]. https://doi.org/10.1038/ncomms9681

An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. / Baskaran, Yohendran; Ang, Khay C.; Anekal, Praju V.; Chan, Wee L.; Grimes, Jonathan M.; Manser, Ed; Robinson, Robert C.

In: Nature communications, Vol. 6, 8681, 26.11.2015.

Research output: Contribution to journalArticle

Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E et al. An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Nature communications. 2015 Nov 26;6. 8681. https://doi.org/10.1038/ncomms9681
Baskaran, Yohendran ; Ang, Khay C. ; Anekal, Praju V. ; Chan, Wee L. ; Grimes, Jonathan M. ; Manser, Ed ; Robinson, Robert C. / An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. In: Nature communications. 2015 ; Vol. 6.
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