Journal:Acta Cryst D:S2059798324005461

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<StructureSection load='' size='450' side='right' scene='underdevelopment' caption=''>
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<StructureSection load='' size='400' side='right' scene='10/1050894/2p2n/2' caption=''>__NOTOC__
===Toward a dependable data set of structures for L-asparaginase===
===Toward a dependable data set of structures for L-asparaginase===
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<big>Alexander Wlodawer, Mariusz Jaskolski</big> <ref>doi: 10.1107/S2059798324005461</ref>
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<big>Alexander Wlodawer, Zbigniew Dauter, Jacek Lubkowski, Joanna I. Loch, Dariusz Brzezinski, Miroslaw Gilski, Mariusz Jaskolski</big> <ref name="dependable">PMID:38935343</ref>
<hr/>
<hr/>
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<b>Molecular Tour</b><br>
 
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<b>Refined Structures</b><br>
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==Function==
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L-Asparaginases are enzymes that hydrolyze the amide group of the amino acid L-asparagine (L-Asn) to L-aspartate, with the simultaneous release of ammonia. They are often referred to as ASNase and assigned the EC number 3.5.1.1; if significant glutaminase co-activity (hydrolysis of the similar amino acid L-glutamine) is also present, the EC number is 3.5.1.38. Some ASNases that belong to other classes (see below) are assigned EC 3.4.19.5.
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<b>References</b><br>
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==Relevance==
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Beyond pure academic curiosity, ASNases are also studied because of their potential application as first-line drugs for the treatment of acute lymphoblastic leukemia (ALL)<ref>PMID:27440950</ref><ref>PMID:31552479</ref><ref>PMID:30993718</ref><ref>PMID:31954377</ref>. By clearing L-asparagine from circulation, they starve the L-Asn-dependent malignant cells to death, while sparing the L-Asn-independent healthy cells. The first L-asparaginase introduced for clinical treatment of ALL was Elspar (EcAII from ''E. coli''), followed by Erwinase (ErA from E. chrysanthemi). ASNases are also used in food industry to prevent the formation of acrylamide from L-Asn in fried starch foods<ref>PMID:19388639</ref><ref>PMID:31954377</ref>.
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==Division of ASNases into three classes==
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So far, three completely different structural classes of ASNases have been identified<ref>PMID:34258001</ref>, originally named according to the source organism of their isolation<ref>PMID:17143335</ref>, namely Class 1 (bacterial-type), Class 2 (plant-type), and Class 3 (Rhizobium etli-type). This newer classification is intersected with an older convention, which divided the known enzymes with L-asparaginase activity into five types, since in both, Class 1 and Class 3, two types are distinguished according to their compartmentalization and expression profile. The prototypes of types I and II (in Class 1), and III (in Class 2), are the ''E. coli'' enzymes EcAI (cytosolic), EcAII (periplasmic), and EcAIII (also cytosolic), respectively. The prototypes of types IV and V (Class 3) are the R. etli enzymes ReAIV (constitutive) and ReAV (inducible).
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==Structural studies==
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The first L-asparaginase structure was published and deposited in the PDB in 1993 for the EcAII enzyme<ref>PMID:8434007</ref> and may serve as an example of a <scene name='10/1050894/Ecaii_3eca/4'>Class 1 type II enzyme</scene> '''[[3eca]]'''. Structure of <scene name='10/1050894/2p2n/2'>Class 1 type I enzymes is exemplified by EcAI</scene><ref>PMID:17451745</ref>, whereas <scene name='52/525144/Ecaiii_2zal/4'>Class 2 type III enzymes may be represented by EcAIII</scene><ref>PMID:15159592</ref><ref>PMID:18334484</ref>. Class 2 L-asparaginases belong to the family of Ntn-hydrolases, which are expressed as inactive precursors that must undergo autoproteolytic cleavage into α and β subunits to achieve maturation<ref>PMID:35626629</ref>. While the existence of an alien type of ASNase in the symbiotic nitrogen-fixing bacterium Rhizobium etli had been recognized long ago<ref>PMID:11996000</ref>, the structure of the inducible and thermolabile prototype <scene name='10/1050894/Reav_7os5/2'>Class 3 ReAV</scene> was solved and deposited in the PDB only recently<ref>PMID:34795296</ref>, followed by structures of the constitutive and thermostable isoform ReAIV<ref>PMID:37494066</ref>. More than 200 structures of ASNases have been deposited in the Protein Data Bank (PDB) by April 2024<ref>PMID:34060231</ref><ref name="dependable"/>.
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==Evaluation of the ASNase structures in the PDB==
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Evaluation of 189 structures of ASNases that were present in the PDB as of November 2023 was described in Wlodawer et al. (2024)</ref><ref name="dependable"/>. Most structures did not raise any significant concerns. However, 30 models had various kinds of stereochemical problems and/or doubtful agreement with the experimental electron density maps. Consequently, they were re-refined in order to remove the shortcomings. An example can be seen in the high-resolution structure of Elspar, where the electron density maps clearly indicated substitutions, ''e.g.'',
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<scene name='10/1056097/Fig_4a/2'>V27A</scene> and <scene name='10/1056097/Fig_4b/4'>S252T</scene>.
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The revised models (listed here) may be downloaded from this site in both the legacy PDB and mmCIF formats.
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==Dependable Structures==
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<jmol><jmolMenu>
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<item><text>Select dependable structure</text>
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<script>zap;</script>
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</item>
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 +
<item>
 +
<text>1agx</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1agx"; "/cgi-bin/pprspt?PDB id [[1agx]]";
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</script>
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</item>
 +
 
 +
<item>
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<text>1nns</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1nns"; "/cgi-bin/pprspt?PDBid [[1nns]]";
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 +
</script>
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</item>
 +
 
 +
<item>
 +
<text>1o7j</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1o7j"; "/cgi-bin/pprspt?PDBid [[1o7j]]";
 +
 
 +
</script>
 +
</item>
 +
 
 +
<item>
 +
<text>1wls</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1wls"; "/cgi-bin/pprspt?PDBid [[1wls]]";
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 +
</script>
 +
</item>
 +
 
 +
<item>
 +
<text>1zcf</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1zcf"; "/cgi-bin/pprspt?PDBid [[1zcf]]";
 +
 
 +
</script>
 +
</item>
 +
 
 +
<item>
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<text>2gvn</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2gvn"; "/cgi-bin/pprspt?PDBid [[2gvn]]";
 +
 
 +
</script>
 +
</item>
 +
 
 +
<item>
 +
<text>2jk0</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2jk0"; "/cgi-bin/pprspt?PDBid [[2jk0]]";
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 +
</script>
 +
</item>
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 +
<item>
 +
<text>2wlt</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2wlt"; "/cgi-bin/pprspt?PDBid [[2wlt]]";
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 +
</script>
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</item>
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 +
<item>
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<text>3pga</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/3pga"; "/cgi-bin/pprspt?PDBid [[3pga]]";
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 +
</script>
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</item>
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 +
<item>
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<text>4o47</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4o47"; "/cgi-bin/pprspt?PDBid [[4o47]]";
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 +
</script>
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</item>
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 +
<item>
 +
<text>4q0m</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4q0m"; "/cgi-bin/pprspt?PDBid [[4q0m]]";
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 +
</script>
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</item>
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 +
<item>
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<text>5b74</text>
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<script>zap;
 +
load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5b74"; "/cgi-bin/pprspt?PDBid [[5b74]]";
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 +
</script>
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</item>
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 +
<item>
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<text>5k3o</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k3o"; "/cgi-bin/pprspt?PDBid [[5k3o]]";
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 +
</script>
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</item>
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 +
<item>
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<text>5k45</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k45"; "/cgi-bin/pprspt?PDBid [[5k45]]";
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 +
</script>
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</item>
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 +
<item>
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<text>5k4g</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k4g"; "/cgi-bin/pprspt?PDBid [[5k4g]]";
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</script>
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</item>
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 +
<item>
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<text>5mq5</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5mq5"; "/cgi-bin/pprspt?PDBid [[5mq5]]";
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</script>
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</item>
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 +
<item>
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<text>5ot0</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5ot0"; "/cgi-bin/pprspt?PDBid [[5ot0]]";
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</script>
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</item>
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<item>
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<text>6rud</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6rud"; "/cgi-bin/pprspt?PDBid [[6rud]]";
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 +
</script>
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</item>
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 +
<item>
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<text>6ruf</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6ruf"; "/cgi-bin/pprspt?PDBid [[6ruf]]";
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 +
</script>
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</item>
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 +
<item>
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<text>6syh</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6syh"; "/cgi-bin/pprspt?PDBid [[6syh]]";
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</script>
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</item>
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 +
<item>
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<text>6uog</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6uog"; "/cgi-bin/pprspt?PDBid [[6uog]]";
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 +
</script>
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</item>
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<item>
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<text>6v5f</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6v5f"; "/cgi-bin/pprspt?PDBid [[6v5f]]";
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</script>
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</item>
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<item>
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<text>6wz6</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6wz6"; "/cgi-bin/pprspt?PDBid [[6wz6]]";
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 +
</script>
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</item>
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<item>
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<text>7a0u</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7a0u"; "/cgi-bin/pprspt?PDBid [[7a0u]]";
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</script>
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</item>
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<item>
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<text>7p9c</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7p9c"; "/cgi-bin/pprspt?PDBid [[7p9c]]";
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</script>
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</item>
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 +
<item>
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<text>7r57</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r57"; "/cgi-bin/pprspt?PDBid [[7r57]]";
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</script>
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</item>
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<item>
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<text>7r5q</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r5q"; "/cgi-bin/pprspt?PDBid [[7r5q]]";
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</script>
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</item>
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<item>
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<text>7u6m</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7u6m"; "/cgi-bin/pprspt?PDBid [[7u6m]]";
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</script>
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</item>
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<item>
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<text>8ecd</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8ecd"; "/cgi-bin/pprspt?PDBid [[8ecd]]";
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</script>
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</item>
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<item>
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<text>8h48</text>
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<script>zap;
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load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8h48"; "/cgi-bin/pprspt?PDBid [[8h48]]";
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 +
</script>
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</item>
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 +
</jmolMenu></jmol>
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<jmol>
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<jmolButton>
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<script>!exit; select:A; hide selected; select:B; display selected;</script>
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<text>show dependable structure</text>
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</jmolButton>
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 +
<jmolButton>
 +
<script>select:B; hide selected; select:A; display selected;</script>
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<text>show deposited structure</text>
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</jmolButton>
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</jmol>
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 +
<jmol>
 +
<jmolButton>
 +
<script>select all; display selected;</script>
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<text>show both structures</text>
 +
</jmolButton>
 +
</jmol>
 +
 
 +
Download <span class="plainlinks alert">[https://proteopedia.org/cgi-bin/pprstr?dwnl/d Deposited] [https://proteopedia.org/cgi-bin/pprstr?dwnl/p Dependable] [https://proteopedia.org/cgi-bin/pprstr?dwnl/a Aligned]</span>
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==References==
<references/>
<references/>
</StructureSection>
</StructureSection>
__NOEDITSECTION__
__NOEDITSECTION__

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