9ec2

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
m (Protected "9ec2" [edit=sysop:move=sysop])
Current revision (10:31, 12 March 2025) (edit) (undo)
 
Line 1: Line 1:
-
'''Unreleased structure'''
 
-
The entry 9ec2 is ON HOLD
+
==Crystal structure of SAMHD1 dimer bound to an inhibitor obtained from high-throughput chemical tethering to the guanine antiviral acyclovir==
 +
<StructureSection load='9ec2' size='340' side='right'caption='[[9ec2]], [[Resolution|resolution]] 2.72&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[9ec2]] is a 4 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=9EC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9EC2 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]] 2.72&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BHL:N-[5-({2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl}amino)-5-oxopentyl]-4,7-dibromo-3-hydroxynaphthalene-2-carboxamide'>A1BHL</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</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=9ec2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ec2 OCA], [https://pdbe.org/9ec2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ec2 RCSB], [https://www.ebi.ac.uk/pdbsum/9ec2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ec2 ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/SAMH1_HUMAN SAMH1_HUMAN] Defects in SAMHD1 are the cause of Aicardi-Goutieres syndrome type 5 (AGS5) [MIM:[https://omim.org/entry/612952 612952]. A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.<ref>PMID:19525956</ref> <ref>PMID:20842748</ref> Defects in SAMHD1 are the cause of chilblain lupus type 2 (CHBL2) [MIM:[https://omim.org/entry/614415 614415]. A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.<ref>PMID:21204240</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/SAMH1_HUMAN SAMH1_HUMAN] Putative nuclease involved in innate immune response by acting as a negative regulator of the cell-intrinsic antiviral response. May play a role in mediating proinflammatory responses to TNF-alpha signaling.<ref>PMID:18546154</ref> <ref>PMID:19525956</ref>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is an enzyme with diverse activities. Its dNTPase activity degrades all canonical dNTPs and many anticancer nucleoside drugs, while its single-stranded nucleic acid binding activity promotes DNA repair and RNA homeostasis in cells. These functions require guanine nucleotide binding to a specific allosteric site (A1) on the enzyme. We previously described how the activities of SAMHD1 could be inhibited in vitro with fragment-based inhibitor design, using dGMP as a targeting fragment for the A1 site. However, these dGMP-tethered inhibitors had poor cell permeability due to the charged guanine monophosphate group. Here, we describe a new approach where the amino form of the guanine acyclic nucleoside acyclovir (NH(2)-ACV) is used as the targeting fragment, allowing facile coupling to activated carboxylic acids (R-COOH), either directly or using linkers. This approach generates a neutral amide instead of charged monophosphate attachment points. High-throughput screening of a approximately 375 compound carboxylic acid library identified two compounds (8, 11) with similar micromolar affinities for SAMHD1. Compound 11 was obtained by direct coupling to NH(2)-ACV, while compound 8 used a five-carbon linker. Both inhibitors had the same dibromonaphthol component from the carboxylic acid library screen. A crystal structure of a complex between SAMHD1 and 8, combined with computational models of bound 11, suggest how the dibromonaphthol promotes binding. The findings establish that guanine-based inhibitors targeting the A1 site do not require nucleotide or cyclic nucleoside structural elements. This guanine site targeting strategy is highly amenable to further chemical optimization.
-
Authors: Egleston, M., Dong, L., Howlader, A.H., Bhat, S., Orris, B., Lopez-Rovira, L.M., Bianchet, M.A., Greenberg, M.M., Stivers, J.T.
+
Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir.,Egleston M, Bhat S, Howlader AH, Bianchet MA, Liu Y, Lopez Rovira LM, Smith B, Greenberg MM, Stivers JT Biochemistry. 2025 Mar 4;64(5):1109-1120. doi: 10.1021/acs.biochem.4c00854. Epub , 2025 Feb 24. PMID:39989431<ref>PMID:39989431</ref>
-
Description: Crystal structure of SAMHD1 dimer bound to an inhibitor obtained from high-throughput chemical tethering to the guanine antiviral acyclovir
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[Category: Unreleased Structures]]
+
</div>
-
[[Category: Bhat, S]]
+
<div class="pdbe-citations 9ec2" style="background-color:#fffaf0;"></div>
-
[[Category: Dong, L]]
+
== References ==
-
[[Category: Egleston, M]]
+
<references/>
-
[[Category: Stivers, J.T]]
+
__TOC__
-
[[Category: Orris, B]]
+
</StructureSection>
-
[[Category: Lopez-Rovira, L.M]]
+
[[Category: Homo sapiens]]
-
[[Category: Howlader, A.H]]
+
[[Category: Large Structures]]
-
[[Category: Bianchet, M.A]]
+
[[Category: Bhat S]]
-
[[Category: Greenberg, M.M]]
+
[[Category: Bianchet MA]]
 +
[[Category: Dong L]]
 +
[[Category: Egleston M]]
 +
[[Category: Greenberg MM]]
 +
[[Category: Howlader AH]]
 +
[[Category: Lopez-Rovira LM]]
 +
[[Category: Orris B]]
 +
[[Category: Stivers JT]]

Current revision

Crystal structure of SAMHD1 dimer bound to an inhibitor obtained from high-throughput chemical tethering to the guanine antiviral acyclovir

PDB ID 9ec2

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9ec2"
Personal tools