13lv: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The~~ entry ~~13lv~~ is ~~ON HOLD~~

==Structure of PKMYT1 bound to allosteric inhibitor P29-(S)==

== Structural highlights ==

<table><tr><td colspan='2'>[[13lv]] is a 1 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=13LV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=13LV 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]] 2.22Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1DG4:(4~{S})-1-cyclopentyl-4-(4-hydroxyphenyl)-5,7-dihydro-4~{H}-pyrazolo[3,4-b]pyridin-6-one'>A1DG4</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=13lv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=13lv OCA], [https://pdbe.org/13lv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=13lv RCSB], [https://www.ebi.ac.uk/pdbsum/13lv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=13lv ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/PMYT1_HUMAN PMYT1_HUMAN] Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.<ref>PMID:9001210</ref> <ref>PMID:10373560</ref>

== Publication Abstract from PubMed ==

The protein kinase PKMYT1 regulates a key cell cycle checkpoint as part of the cell's DNA-damage repair response, but in cancer, this function can promote tumor cell survival through avoiding mitotic catastrophe. PKMYT1 has been linked to a variety of cancer types, including breast, gastric, and nonsmall cell lung cancers, as well as kidney renal clear cell carcinoma, making it an important therapeutic target. However, potent and selective small-molecule inhibitors of PKMYT1 are scarce, and its specific biological role in tumor proliferation remains understudied. Here, we report the discovery and characterization of a novel PKMYT1 inhibitor, P29, bound to a previously unknown allosteric site. Structural and kinetic data reveal that P29 induces a conformational rearrangement of the P-loop and inhibits PKMYT1 through a mixed ATP competitive and noncompetitive mechanism. A closely related analogue, P32, exhibits selectivity and enhanced potency and engages PKMYT1 in cells. Surprisingly, however, it binds in the ATP binding pocket, demonstrating that subtle chemical modifications can shift binding mode and mechanism of inhibition. Furthermore, computational analysis using structural modeling methods, including AlphaFold2, AlphaFold3, Boltz-2, as well as unbiased MD simulations, indicates that these approaches are limited in their ability to capture this inhibitor-induced cryptic binding site and conformational change. Our study identifies an underexplored allosteric site in PKMYT1 and establishes a new avenue for the rational design of selective kinase inhibitors targeting a cryptic binding site in this emerging drug target. These findings also reveal intrinsic challenges in the computational discovery of noncanonical kinase binding sites and underscore the necessity of integrating computational modeling with experimental testing using structural and functional approaches.

~~Authors:~~ Khamrui, S., Lazarus, M.B.

Allosteric Inhibition of PKMYT1 Induces a Unique, Inactive ATP Binding Site Conformation.,Herrington NB, Khamrui S, Zhao Y, Lansiquot C, Wu R, Pandey G, Lazarus MB, Schlessinger A J Am Chem Soc. 2026 Jun 2. doi: 10.1021/jacs.6c05178. PMID:42227652<ref>PMID:42227652</ref>

~~Description: Structure~~ of ~~PKMYT1 bound to allosteric inhibitor P29~~-~~(S)~~

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

[[Category: ~~Unreleased Structures~~]]

</div>

[[Category: ~~Lazarus, M.B~~]]

[[Category: Khamrui, S]]

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Khamrui S]]

[[Category: Lazarus MB]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 13lv is ON HOLD
+==Structure of PKMYT1 bound to allosteric inhibitor P29-(S)==
+<StructureSection load='13lv' size='340' side='right'caption='[[13lv]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[13lv]] is a 1 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=13LV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=13LV 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]] 2.22&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1DG4:(4~{S})-1-cyclopentyl-4-(4-hydroxyphenyl)-5,7-dihydro-4~{H}-pyrazolo[3,4-b]pyridin-6-one'>A1DG4</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=13lv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=13lv OCA], [https://pdbe.org/13lv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=13lv RCSB], [https://www.ebi.ac.uk/pdbsum/13lv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=13lv ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PMYT1_HUMAN PMYT1_HUMAN] Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.<ref>PMID:9001210</ref> <ref>PMID:10373560</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The protein kinase PKMYT1 regulates a key cell cycle checkpoint as part of the cell's DNA-damage repair response, but in cancer, this function can promote tumor cell survival through avoiding mitotic catastrophe. PKMYT1 has been linked to a variety of cancer types, including breast, gastric, and nonsmall cell lung cancers, as well as kidney renal clear cell carcinoma, making it an important therapeutic target. However, potent and selective small-molecule inhibitors of PKMYT1 are scarce, and its specific biological role in tumor proliferation remains understudied. Here, we report the discovery and characterization of a novel PKMYT1 inhibitor, P29, bound to a previously unknown allosteric site. Structural and kinetic data reveal that P29 induces a conformational rearrangement of the P-loop and inhibits PKMYT1 through a mixed ATP competitive and noncompetitive mechanism. A closely related analogue, P32, exhibits selectivity and enhanced potency and engages PKMYT1 in cells. Surprisingly, however, it binds in the ATP binding pocket, demonstrating that subtle chemical modifications can shift binding mode and mechanism of inhibition. Furthermore, computational analysis using structural modeling methods, including AlphaFold2, AlphaFold3, Boltz-2, as well as unbiased MD simulations, indicates that these approaches are limited in their ability to capture this inhibitor-induced cryptic binding site and conformational change. Our study identifies an underexplored allosteric site in PKMYT1 and establishes a new avenue for the rational design of selective kinase inhibitors targeting a cryptic binding site in this emerging drug target. These findings also reveal intrinsic challenges in the computational discovery of noncanonical kinase binding sites and underscore the necessity of integrating computational modeling with experimental testing using structural and functional approaches.
-Authors: Khamrui, S., Lazarus, M.B.
+Allosteric Inhibition of PKMYT1 Induces a Unique, Inactive ATP Binding Site Conformation.,Herrington NB, Khamrui S, Zhao Y, Lansiquot C, Wu R, Pandey G, Lazarus MB, Schlessinger A J Am Chem Soc. 2026 Jun 2. doi: 10.1021/jacs.6c05178. PMID:42227652<ref>PMID:42227652</ref>
-Description: Structure of PKMYT1 bound to allosteric inhibitor P29-(S)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lazarus, M.B]]
+<div class="pdbe-citations 13lv" style="background-color:#fffaf0;"></div>
-[[Category: Khamrui, S]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Khamrui S]]
+[[Category: Lazarus MB]]