First time at Proteopedia? Click on the green links: they change the 3D image. Click and drag the molecules. Proteopedia is a 3D, interactive encyclopedia of proteins, RNA, DNA and other molecules. With a free user account, you can edit pages in Proteopedia. Visit the Main Page to learn more.
3qrk
From Proteopedia
| 3qrk, resolution 2.30Å () | |
|---|---|
| Ligands: | |
| Gene: | ABL1, ABL, JTK7 (Homo sapiens) |
| Activity: | Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 |
| Related: | 3qri, 3qrj
|
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
| Coordinates: | save as pdb, mmCIF, xml |
The crystal structure of human abl1 kinase domain in complex with DP-987
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036., Chan WW, Wise SC, Kaufman MD, Ahn YM, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu WP, Miller D, Patt WC, Smith BD, Petillo PA, Rutkoski TJ, Telikepalli H, Vogeti L, Yao T, Chun L, Clark R, Evangelista P, Gavrilescu LC, Lazarides K, Zaleskas VM, Stewart LJ, Van Etten RA, Flynn DL, Cancer Cell. 2011 Apr 12;19(4):556-68. PMID:21481795
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
3qrk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Chan WW, Wise SC, Kaufman MD, Ahn YM, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu WP, Miller D, Patt WC, Smith BD, Petillo PA, Rutkoski TJ, Telikepalli H, Vogeti L, Yao T, Chun L, Clark R, Evangelista P, Gavrilescu LC, Lazarides K, Zaleskas VM, Stewart LJ, Van Etten RA, Flynn DL. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011 Apr 12;19(4):556-68. PMID:21481795 doi:10.1016/j.ccr.2011.03.003
Categories: Homo sapiens | Non-specific protein-tyrosine kinase | Ahn, Y M. | Chan, W W. | Chun, L. | Clark, R. | Ensinger, C L. | Etten, R A.Van. | Evangelista, P. | Flynn, D L. | Gavrilescu, L C. | Haack, T. | Hood, M M. | Jones, J. | Kaufman, M D. | Lazarides, K. | Lord, J W. | Lu, W P. | Miller, D. | Patt, W C. | Petillo, P A. | Rutkoski, T J. | Smith, B D. | Stewart, L J. | Telikepalli, H. | Vogeti, L. | Wise, S C. | Yao, T. | Zaleskas, V M.
