1d6n: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1d6n.jpg|left|200px]]<br /><applet load="1d6n" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="1d6n, resolution 2.70&Aring;" />
-'''TERNARY COMPLEX STRUCTURE OF HUMAN HGPRTASE, PRPP, MG2+, AND THE INHIBITOR HPP REVEALS THE INVOLVEMENT OF THE FLEXIBLE LOOP IN SUBSTRATE BINDING'''<br />
-==Overview==
+==TERNARY COMPLEX STRUCTURE OF HUMAN HGPRTASE, PRPP, MG2+, AND THE INHIBITOR HPP REVEALS THE INVOLVEMENT OF THE FLEXIBLE LOOP IN SUBSTRATE BINDING==
-Site-directed mutagenesis was used to replace Lys68 of the human, hypoxanthine phosphoribosyltransferase (HGPRTase) with alanine to exploit, this less reactive form of the enzyme to gain additional insights into the, structure activity relationship of HGPRTase. Although this substitution, resulted in only a minimal (one- to threefold) increase in the Km values, for binding pyrophosphate or phosphoribosylpyrophosphate, the catalytic, efficiencies (k(cat)/Km) of the forward and reverse reactions were more, severely reduced (6- to 30-fold), and the mutant enzyme showed positive, cooperativity in binding of alpha-D-5-phosphoribosyl-1-pyrophosphate, (PRPP) and nucleotide. The K68A form of the human HGPRTase was, cocrystallized with 7-hydroxy [4,3-d] pyrazolo pyrimidine (HPP) and Mg, PRPP, and the refined structure reported. The PRPP molecule built into the, [(Fo - Fc)phi(calc)] electron density shows atomic interactions between, the Mg PRPP and enzyme residues in the pyrophosphate binding domain as, well as in a long flexible loop (residues Leu101 to Gly111) that closes, over the active site. Loop closure reveals the functional roles for the, conserved SY dipeptide of the loop as well as the molecular basis for one, form of gouty arthritis (S103R). In addition, the closed loop conformation, provides structural information relevant to the mechanism of catalysis in, human HGPRTase.
+<StructureSection load='1d6n' size='340' side='right'caption='[[1d6n]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1d6n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The July 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)''  by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_7 10.2210/rcsb_pdb/mom_2012_7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D6N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D6N 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]] 2.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PPO:3H-PYRAZOLO[4,3-D]PYRIMIDIN-7-OL'>PPO</scene>, <scene name='pdbligand=PRP:ALPHA-PHOSPHORIBOSYLPYROPHOSPHORIC+ACID'>PRP</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=1d6n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d6n OCA], [https://pdbe.org/1d6n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d6n RCSB], [https://www.ebi.ac.uk/pdbsum/1d6n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d6n ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[https://omim.org/entry/300322 300322]. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.<ref>PMID:6853716</ref> <ref>PMID:3384338</ref> <ref>PMID:3265398</ref> <ref>PMID:2910902</ref> <ref>PMID:2347587</ref> <ref>PMID:2358296</ref> <ref>PMID:2246854</ref> <ref>PMID:2071157</ref> <ref>PMID:7627191</ref> <ref>PMID:9452051</ref>   Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:[https://omim.org/entry/300323 300323]; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.<ref>PMID:6853490</ref> <ref>PMID:6572373</ref> <ref>PMID:6706936</ref> <ref>PMID:3358423</ref> <ref>PMID:3198771</ref> <ref>PMID:2909537</ref> [:]
+== Function ==
+[https://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN] Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d6/1d6n_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1d6n ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known diseases associated with this structure: HPRT-related gout OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=308000 308000]], Lesch-Nyhan syndrome, 300322, OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=308000 308000]]
+*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-D6N is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=PPO:'>PPO</scene> and <scene name='pdbligand=PRP:'>PRP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hypoxanthine_phosphoribosyltransferase Hypoxanthine phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.8 2.4.2.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D6N OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Ternary complex structure of human HGPRTase, PRPP, Mg2+, and the inhibitor HPP reveals the involvement of the flexible loop in substrate binding., Balendiran GK, Molina JA, Xu Y, Torres-Martinez J, Stevens R, Focia PJ, Eakin AE, Sacchettini JC, Craig SP 3rd, Protein Sci. 1999 May;8(5):1023-31. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10338013 10338013]
 [[Category: Homo sapiens]]
-[[Category: Hypoxanthine phosphoribosyltransferase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: RCSB PDB Molecule of the Month]]
-[[Category: Balendiran, G.K.]]
+[[Category: Balendiran GK]]
-[[Category: MG]]
-[[Category: PPO]]
-[[Category: PRP]]
-[[Category: hgprtase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 15:38:48 2008''