Related Experiment Video
Updated: Jun 19, 2026
X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
Published on: May 13, 2020
Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor
Alex N Bullock1, Santina Russo, Ann Amos
1University of Oxford, Structural Genomics Consortium, Oxford, United Kingdom.
Background:
The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2.
Principal Findings:
Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases.
Significance:
The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors.
Enhanced Version:
This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Insights
Researchers determined the crystal structure of serine/threonine kinase PIM2, a target in leukemia and lymphoma. A potent organoruthenium inhibitor was developed, offering insights for novel anticancer drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas.
- PIM2 regulates tumor cell survival and proliferation, making it a promising anticancer target.
- Limited structural data exists for PIM kinase family catalytic domains, with PIM1 being the most studied.
Purpose of the Study:
- To determine the crystal structure of PIM2.
- To investigate PIM2 inhibition using an organoruthenium complex.
- To explore PIM2 structure for developing isoform-selective inhibitors.
Main Methods:
- X-ray crystallography to determine the PIM2-inhibitor complex structure.
- Biochemical assays to assess inhibition potency (sub-nanomolar).
Main Results:
- The crystal structure of PIM2 in complex with an organoruthenium compound was determined.
- The organoruthenium complex demonstrated potent inhibition of PIM kinases at sub-nanomolar levels.
- Significant structural differences between PIM2 and PIM1 were identified.
Conclusions:
- The determined PIM2 structure reveals differences from PIM1, enabling the design of isoform-selective inhibitors.
- Organometallic inhibitors can be effectively adapted to protein kinase binding sites for high potency.
- This study provides a structural basis for developing novel PIM2-targeted anticancer therapies.
