8t09

From Proteopedia

(Difference between revisions)

Current revision

Co-crystal structure of KRIT1 with a 1-hydroxy 2-naphthaldehyde derivative (6-ethynyl-2-hydroxy-1-naphthaldehyde)

Structural highlights

8t09 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 2.15Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KRIT1_HUMAN Hereditary cerebral cavernous malformation. Cerebral cavernous malformations 1 (CCM1) [MIM:116860: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Note=The disease is caused by mutations affecting the gene represented in this entry.^[1]

Function

KRIT1_HUMAN Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.^[2] ^[3] ^[4] ^[5] [REFERENCE:17]

Publication Abstract from PubMed

The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys(720)) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)-KRIT1 protein-protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines.

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.,Francisco KR, Bruystens J, Varricchio C, McCurdy S, Wu J, Lopez-Ramirez MA, Ginsberg M, Caffrey CR, Brancale A, Gingras AR, Hixon MS, Ballatore C ACS Pharmacol Transl Sci. 2023 Oct 9;6(11):1651-1658. doi: , 10.1021/acsptsci.3c00156. eCollection 2023 Nov 10. PMID:37974623^[6]

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

References

↑ Kehrer-Sawatzki H, Wilda M, Braun VM, Richter HP, Hameister H. Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1). Acta Neuropathol. 2002 Sep;104(3):231-40. Epub 2002 Jun 26. PMID:12172908 doi:10.1007/s00401-002-0552-6
↑ Lampugnani MG, Orsenigo F, Rudini N, Maddaluno L, Boulday G, Chapon F, Dejana E. CCM1 regulates vascular-lumen organization by inducing endothelial polarity. J Cell Sci. 2010 Apr 1;123(Pt 7):1073-80. doi: 10.1242/jcs.059329. PMID:20332120 doi:10.1242/jcs.059329
↑ Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, Retta SF. KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PLoS One. 2010 Jul 26;5(7):e11786. doi: 10.1371/journal.pone.0011786. PMID:20668652 doi:10.1371/journal.pone.0011786
↑ Wustehube J, Bartol A, Liebler SS, Brutsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12640-5. doi:, 10.1073/pnas.1000132107. Epub 2010 Jun 24. PMID:20616044 doi:10.1073/pnas.1000132107
↑ Liu JJ, Stockton RA, Gingras AR, Ablooglu AJ, Han J, Bobkov AA, Ginsberg MH. A mechanism of Rap1-induced stabilization of endothelial cell--cell junctions. Mol Biol Cell. 2011 Jul 15;22(14):2509-19. doi: 10.1091/mbc.E11-02-0157. Epub, 2011 Jun 1. PMID:21633110 doi:10.1091/mbc.E11-02-0157
↑ Francisco KR, Bruystens J, Varricchio C, McCurdy S, Wu J, Lopez-Ramirez MA, Ginsberg M, Caffrey CR, Brancale A, Gingras AR, Hixon MS, Ballatore C. Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors. ACS Pharmacol Transl Sci. 2023 Oct 9;6(11):1651-1658. PMID:37974623 doi:10.1021/acsptsci.3c00156

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8t09"

Categories: Homo sapiens | Large Structures | Bruystens JGH

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8t09]] 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=8T09 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8T09 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]] 2.15&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=XHZ:6-ethynyl-2-hydroxynaphthalene-1-carbaldehyde'>XHZ</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=XHZ:6-ethynyl-2-oxidanyl-naphthalene-1-carbaldehyde'>XHZ</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=8t09 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8t09 OCA], [https://pdbe.org/8t09 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8t09 RCSB], [https://www.ebi.ac.uk/pdbsum/8t09 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8t09 ProSAT]</span></td></tr>
 </table>

8t09

From Proteopedia

Current revision

Co-crystal structure of KRIT1 with a 1-hydroxy 2-naphthaldehyde derivative (6-ethynyl-2-hydroxy-1-naphthaldehyde)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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