5otf

MRCK beta in complex with BDP-00009066MRCK beta in complex with BDP-00009066

Structural highlights

5otf is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MRCKB_HUMAN Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The myotonic dystrophy-related Cdc42-binding kinases MRCKalpha and MRCKbeta contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKalpha S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKalpha status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKalpha S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.,Unbekandt M, Belshaw S, Bower J, Clarke M, Cordes J, Crighton D, Croft DR, Drysdale MJ, Garnett MJ, Gill K, Gray C, Greenhalgh DA, Hall JA, Konczal J, Lilla S, McArthur D, McConnell P, McDonald L, McGarry L, McKinnon H, McMenemy C, Mezna M, Morrice NA, Munro J, Naylor G, Rath N, Schuttelkopf AW, Sime M, Olson MF Cancer Res. 2018 Jan 30. pii: 0008-5472.CAN-17-2870. doi:, 10.1158/0008-5472.CAN-17-2870. PMID:29382705^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tan I, Yong J, Dong JM, Lim L, Leung T. A tripartite complex containing MRCK modulates lamellar actomyosin retrograde flow. Cell. 2008 Oct 3;135(1):123-36. doi: 10.1016/j.cell.2008.09.018. PMID:18854160 doi:http://dx.doi.org/10.1016/j.cell.2008.09.018
↑ Tan I, Lai J, Yong J, Li SF, Leung T. Chelerythrine perturbs lamellar actomyosin filaments by selective inhibition of myotonic dystrophy kinase-related Cdc42-binding kinase. FEBS Lett. 2011 May 6;585(9):1260-8. doi: 10.1016/j.febslet.2011.03.054. Epub, 2011 Mar 30. PMID:21457715 doi:10.1016/j.febslet.2011.03.054
↑ Heikkila T, Wheatley E, Crighton D, Schroder E, Boakes A, Kaye SJ, Mezna M, Pang L, Rushbrooke M, Turnbull A, Olson MF. Co-crystal structures of inhibitors with MRCKbeta, a key regulator of tumor cell invasion. PLoS One. 2011;6(9):e24825. Epub 2011 Sep 20. PMID:21949762 doi:10.1371/journal.pone.0024825
↑ Unbekandt M, Belshaw S, Bower J, Clarke M, Cordes J, Crighton D, Croft DR, Drysdale MJ, Garnett MJ, Gill K, Gray C, Greenhalgh DA, Hall JA, Konczal J, Lilla S, McArthur D, McConnell P, McDonald L, McGarry L, McKinnon H, McMenemy C, Mezna M, Morrice NA, Munro J, Naylor G, Rath N, Schuttelkopf AW, Sime M, Olson MF. Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Cancer Res. 2018 Jan 30. pii: 0008-5472.CAN-17-2870. doi:, 10.1158/0008-5472.CAN-17-2870. PMID:29382705 doi:http://dx.doi.org/10.1158/0008-5472.CAN-17-2870

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Tan I, Yong J, Dong JM, Lim L, Leung T. A tripartite complex containing MRCK modulates lamellar actomyosin retrograde flow. Cell. 2008 Oct 3;135(1):123-36. doi: 10.1016/j.cell.2008.09.018. PMID:18854160 doi:http://dx.doi.org/10.1016/j.cell.2008.09.018

[2] Tan I, Lai J, Yong J, Li SF, Leung T. Chelerythrine perturbs lamellar actomyosin filaments by selective inhibition of myotonic dystrophy kinase-related Cdc42-binding kinase. FEBS Lett. 2011 May 6;585(9):1260-8. doi: 10.1016/j.febslet.2011.03.054. Epub, 2011 Mar 30. PMID:21457715 doi:10.1016/j.febslet.2011.03.054

[3] Heikkila T, Wheatley E, Crighton D, Schroder E, Boakes A, Kaye SJ, Mezna M, Pang L, Rushbrooke M, Turnbull A, Olson MF. Co-crystal structures of inhibitors with MRCKbeta, a key regulator of tumor cell invasion. PLoS One. 2011;6(9):e24825. Epub 2011 Sep 20. PMID:21949762 doi:10.1371/journal.pone.0024825

[4] Unbekandt M, Belshaw S, Bower J, Clarke M, Cordes J, Crighton D, Croft DR, Drysdale MJ, Garnett MJ, Gill K, Gray C, Greenhalgh DA, Hall JA, Konczal J, Lilla S, McArthur D, McConnell P, McDonald L, McGarry L, McKinnon H, McMenemy C, Mezna M, Morrice NA, Munro J, Naylor G, Rath N, Schuttelkopf AW, Sime M, Olson MF. Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Cancer Res. 2018 Jan 30. pii: 0008-5472.CAN-17-2870. doi:, 10.1158/0008-5472.CAN-17-2870. PMID:29382705 doi:http://dx.doi.org/10.1158/0008-5472.CAN-17-2870

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