8v5i

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of MAP4K4 in complex with an inhibitor

Structural highlights

8v5i is a 2 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 2.18Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

M4K4_HUMAN Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.^[1] ^[2]

Publication Abstract from PubMed

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).,Gallego RA, Scales S, Toledo C, Auth M, Bernier L, Berry M, Brun S, Chung L, Davis C, Diehl W, Dress K, Eisele K, Elleraas J, Ewanicki J, Fobian Y, Greasley S, Greenwald EC, Johnson TW, Khamphavong P, Lafontaine J, Li J, Linton A, Maestre M, Miller N, Murtaza A, Patman RL, Quinlan CL, Ramms DJ, Richardson P, Sach N, Salomon-Ferrer R, Silva F, Timofeevski S, Tran P, Tran-Dube M, Wang F, Wang W, Wythes M, Yang S, Zou A, VanArsdale T, McAlpine I J Med Chem. 2024 Nov 14;67(21):19234-19246. doi: 10.1021/acs.jmedchem.4c01659. , Epub 2024 Nov 5. PMID:39499084^[3]

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

References

↑ Yao Z, Zhou G, Wang XS, Brown A, Diener K, Gan H, Tan TH. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem. 1999 Jan 22;274(4):2118-25. PMID:9890973
↑ Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11127-32. doi:, 10.1073/pnas.1104128108. Epub 2011 Jun 20. PMID:21690388 doi:http://dx.doi.org/10.1073/pnas.1104128108
↑ Gallego RA, Scales S, Toledo C, Auth M, Bernier L, Berry M, Brun S, Chung L, Davis C, Diehl W, Dress K, Eisele K, Elleraas J, Ewanicki J, Fobian Y, Greasley S, Greenwald EC, Johnson TW, Khamphavong P, Lafontaine J, Li J, Linton A, Maestre M, Miller N, Murtaza A, Patman RL, Quinlan CL, Ramms DJ, Richardson P, Sach N, Salomon-Ferrer R, Silva F, Timofeevski S, Tran P, Tran-Dubé M, Wang F, Wang W, Wythes M, Yang S, Zou A, VanArsdale T, McAlpine I. Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL). J Med Chem. 2024 Nov 14;67(21):19234-19246. PMID:39499084 doi:10.1021/acs.jmedchem.4c01659

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8v5i"

Categories: Homo sapiens | Large Structures | Diehl W | Greasley SE

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8v5i is ON HOLD  until Paper Publication
+==Crystal structure of MAP4K4 in complex with an inhibitor==
+<StructureSection load='8v5i' size='340' side='right'caption='[[8v5i]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8v5i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8V5I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8V5I FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AAA:~{N}6-(1,4-dimethylpyrazol-3-yl)-3-(3-methylimidazol-4-yl)-2,7-naphthyridine-1,6-diamine'>A1AAA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8v5i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8v5i OCA], [https://pdbe.org/8v5i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8v5i RCSB], [https://www.ebi.ac.uk/pdbsum/8v5i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8v5i ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/M4K4_HUMAN M4K4_HUMAN] Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.<ref>PMID:9890973</ref> <ref>PMID:21690388</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.
-Authors: Greasley, S.E., Diehl, W.
+Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).,Gallego RA, Scales S, Toledo C, Auth M, Bernier L, Berry M, Brun S, Chung L, Davis C, Diehl W, Dress K, Eisele K, Elleraas J, Ewanicki J, Fobian Y, Greasley S, Greenwald EC, Johnson TW, Khamphavong P, Lafontaine J, Li J, Linton A, Maestre M, Miller N, Murtaza A, Patman RL, Quinlan CL, Ramms DJ, Richardson P, Sach N, Salomon-Ferrer R, Silva F, Timofeevski S, Tran P, Tran-Dube M, Wang F, Wang W, Wythes M, Yang S, Zou A, VanArsdale T, McAlpine I J Med Chem. 2024 Nov 14;67(21):19234-19246. doi: 10.1021/acs.jmedchem.4c01659. , Epub 2024 Nov 5. PMID:39499084<ref>PMID:39499084</ref>
-Description: Crystal structure of MAP4K4 in complex with an inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Diehl, W]]
+<div class="pdbe-citations 8v5i" style="background-color:#fffaf0;"></div>
-[[Category: Greasley, S.E]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Diehl W]]
+[[Category: Greasley SE]]

8v5i

From Proteopedia

Current revision

Crystal structure of MAP4K4 in complex with an inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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