6yvz: Difference between revisions

Latest revision as of 10:46, 23 October 2024

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with bicyclic JLS-367

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.91Å
Ligands:	BCT, MN, PW8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein-protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) readily crystallises as a homotrimer, but with a sterically blocked active site. We explored strategies aimed at altering PHD2 crystal packing by protein modification and molecules that bind at its active site and elsewhere. Following the observation that, despite weak inhibition/binding in solution, succinamic acid derivatives readily enable PHD2 crystallization, we explored methods to induce crystallization without active site binding. Cyclic peptides obtained via mRNA display bind PHD2 tightly away from the active site. They efficiently enable PHD2 crystallization in different forms, both with/without substrates, apparently by promoting oligomerization involving binding to the C-terminal region. Although our work involves a specific case study, together with those of others, the results suggest that mRNA display-derived cyclic peptides may be useful in challenging protein crystallization cases.

Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2.,Chowdhury R, Abboud MI, McAllister TE, Banerji B, Bhushan B, Sorensen JL, Kawamura A, Schofield CJ Sci Rep. 2020 Dec 15;10(1):21964. doi: 10.1038/s41598-020-76307-8. PMID:33319810^[1]

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

References

↑ Chowdhury R, Abboud MI, McAllister TE, Banerji B, Bhushan B, Sorensen JL, Kawamura A, Schofield CJ. Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2. Sci Rep. 2020 Dec 15;10(1):21964. doi: 10.1038/s41598-020-76307-8. PMID:33319810 doi:https://dx.doi.org/10.1038/s41598-020-76307-8

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OCA

[1] Chowdhury R, Abboud MI, McAllister TE, Banerji B, Bhushan B, Sorensen JL, Kawamura A, Schofield CJ. Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2. Sci Rep. 2020 Dec 15;10(1):21964. doi: 10.1038/s41598-020-76307-8. PMID:33319810 doi:https://dx.doi.org/10.1038/s41598-020-76307-8

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6yvz' size='340' side='right'caption='[[6yvz]], [[Resolution|resolution]] 1.91&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6yvz]] 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=6YVZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVZ FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YVZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVZ 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]] 1.91&#8491;</td></tr>
 <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PW8:4-[(5-bromanylisoquinolin-3-yl)amino]-4-oxidanylidene-butanoic+acid'>PW8</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=6yvz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yvz OCA], [https://pdbe.org/6yvz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yvz RCSB], [https://www.ebi.ac.uk/pdbsum/6yvz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yvz ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[https://www.uniprot.org/uniprot/EGLN1_HUMAN EGLN1_HUMAN] Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:[https://omim.org/entry/609820 609820]. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.<ref>PMID:16407130</ref> <ref>PMID:17579185</ref>
-== Function ==
-[https://www.uniprot.org/uniprot/EGLN1_HUMAN EGLN1_HUMAN] Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.<ref>PMID:11595184</ref> <ref>PMID:12351678</ref> <ref>PMID:15897452</ref> <ref>PMID:19339211</ref> <ref>PMID:21792862</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Chowdhury R]]
 [[Category: Schofield CJ]]
 [[Category: Sorensen JL]]

6yvz: Difference between revisions

Latest revision as of 10:46, 23 October 2024

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with bicyclic JLS-367

Structural highlights

Publication Abstract from PubMed

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References

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