4jzr

From Proteopedia

(Difference between revisions)

Revision as of 10:28, 4 August 2016

Structure of Prolyl Hydroxylase Domain-containing Protein (PHD) with Inhibitors

Structural highlights

4jzr is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	C1orf12, EGLN1, PNAS-118, PNAS-137 (HUMAN)
Activity:	Hypoxia-inducible factor-proline dioxygenase, with EC number 1.14.11.29
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EGLN1_HUMAN] Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM: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.^[1] ^[2]

Function

[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.^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a pi-cation interaction with Arg322, a pi-pi stacking with Trp389, and a pi-pi stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice.

Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors.,Deng G, Zhao B, Ma Y, Xu Q, Wang H, Yang L, Zhang Q, Guo TB, Zhang W, Jiao Y, Cai X, Zhang J, Liu H, Guan X, Lu H, Xiang J, Elliott JD, Lin X, Ren F Bioorg Med Chem. 2013 Nov 1;21(21):6349-58. doi: 10.1016/j.bmc.2013.08.046. Epub , 2013 Sep 3. PMID:24055079^[8]

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

References

↑ Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. Epub 2006 Jan 9. PMID:16407130 doi:0508423103
↑ Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007 Sep 15;110(6):2193-6. Epub 2007 Jun 19. PMID:17579185 doi:10.1182/blood-2007-04-084434
↑ Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. PMID:11595184
↑ Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13459-64. Epub 2002 Sep 26. PMID:12351678 doi:10.1073/pnas.192342099
↑ Ozer A, Wu LC, Bruick RK. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005 May 24;102(21):7481-6. Epub 2005 May 16. PMID:15897452 doi:0502716102
↑ Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K. Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009 May;1793(5):792-7. doi: 10.1016/j.bbamcr.2009.01.014. , Epub 2009 Feb 5. PMID:19339211 doi:10.1016/j.bbamcr.2009.01.014
↑ Su Y, Loos M, Giese N, Metzen E, Buchler MW, Friess H, Kornberg A, Buchler P. Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer. 2012 Feb 15;118(4):960-72. doi: 10.1002/cncr.26344. Epub 2011 Jul 26. PMID:21792862 doi:10.1002/cncr.26344
↑ Deng G, Zhao B, Ma Y, Xu Q, Wang H, Yang L, Zhang Q, Guo TB, Zhang W, Jiao Y, Cai X, Zhang J, Liu H, Guan X, Lu H, Xiang J, Elliott JD, Lin X, Ren F. Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors. Bioorg Med Chem. 2013 Nov 1;21(21):6349-58. doi: 10.1016/j.bmc.2013.08.046. Epub , 2013 Sep 3. PMID:24055079 doi:http://dx.doi.org/10.1016/j.bmc.2013.08.046

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/4jzr"

@@ Line 1: / Line 1: @@
 ==Structure of Prolyl Hydroxylase Domain-containing Protein (PHD) with Inhibitors==
 <StructureSection load='4jzr' size='340' side='right' caption='[[4jzr]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4jzr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JZR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4jzr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JZR FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4JR:2-(BIPHENYL-4-YL)-8-[(1-METHYL-1H-IMIDAZOL-2-YL)METHYL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>4JR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">C1orf12, EGLN1, PNAS-118, PNAS-137 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">C1orf12, EGLN1, PNAS-118, PNAS-137 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hypoxia-inducible_factor-proline_dioxygenase Hypoxia-inducible factor-proline dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.29 1.14.11.29] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jzr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jzr RCSB], [http://www.ebi.ac.uk/pdbsum/4jzr PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jzr OCA], [http://pdbe.org/4jzr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jzr RCSB], [http://www.ebi.ac.uk/pdbsum/4jzr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jzr ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4jzr" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Hypoxia-inducible factor-proline dioxygenase]]
 [[Category: Ma, Y]]

4jzr

From Proteopedia

Revision as of 10:28, 4 August 2016

Structure of Prolyl Hydroxylase Domain-containing Protein (PHD) with Inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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