Journal:Acta Cryst D:S2059798324005461
From Proteopedia
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| - | <StructureSection load='' size=' | + | <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=== | ||
| - | <big>Alexander Wlodawer, Zbigniew Dauter, Jacek Lubkowski, Joanna I. Loch, Dariusz Brzezinski, Miroslaw Gilski, Mariusz Jaskolski</big> <ref> | + | <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/> | ||
| Line 8: | Line 8: | ||
==Relevance== | ==Relevance== | ||
| - | 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>. | + | 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>. |
==Division of ASNases into three classes== | ==Division of ASNases into three classes== | ||
| - | 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). | + | 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). |
| + | ==Structural studies== | ||
| + | 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"/>. | ||
| + | |||
| + | ==Evaluation of the ASNase structures in the PDB== | ||
| + | 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.'', | ||
| + | <scene name='10/1056097/Fig_4a/2'>V27A</scene> and <scene name='10/1056097/Fig_4b/4'>S252T</scene>. | ||
| + | |||
| + | The revised models (listed here) may be downloaded from this site in both the legacy PDB and mmCIF formats. | ||
==Dependable Structures== | ==Dependable Structures== | ||
<jmol><jmolMenu> | <jmol><jmolMenu> | ||
<item><text>Select dependable structure</text> | <item><text>Select dependable structure</text> | ||
| - | + | <script>zap;</script> | |
| - | </item> | + | </item> |
| - | + | ||
<item> | <item> | ||
<text>1agx</text> | <text>1agx</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1agx"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1agx"; "/cgi-bin/pprspt?PDB id [[1agx]]"; |
</script> | </script> | ||
</item> | </item> | ||
| Line 30: | Line 37: | ||
<text>1nns</text> | <text>1nns</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1nns"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1nns"; "/cgi-bin/pprspt?PDBid [[1nns]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 37: | Line 45: | ||
<text>1o7j</text> | <text>1o7j</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1o7j"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1o7j"; "/cgi-bin/pprspt?PDBid [[1o7j]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 44: | Line 53: | ||
<text>1wls</text> | <text>1wls</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1wls"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1wls"; "/cgi-bin/pprspt?PDBid [[1wls]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 51: | Line 61: | ||
<text>1zcf</text> | <text>1zcf</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1zcf"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/1zcf"; "/cgi-bin/pprspt?PDBid [[1zcf]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 58: | Line 69: | ||
<text>2gvn</text> | <text>2gvn</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2gvn"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2gvn"; "/cgi-bin/pprspt?PDBid [[2gvn]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 65: | Line 77: | ||
<text>2jk0</text> | <text>2jk0</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2jk0"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2jk0"; "/cgi-bin/pprspt?PDBid [[2jk0]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 72: | Line 85: | ||
<text>2wlt</text> | <text>2wlt</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2wlt"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/2wlt"; "/cgi-bin/pprspt?PDBid [[2wlt]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 79: | Line 93: | ||
<text>3pga</text> | <text>3pga</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/3pga"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/3pga"; "/cgi-bin/pprspt?PDBid [[3pga]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 86: | Line 101: | ||
<text>4o47</text> | <text>4o47</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4o47"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4o47"; "/cgi-bin/pprspt?PDBid [[4o47]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 93: | Line 109: | ||
<text>4q0m</text> | <text>4q0m</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4q0m"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/4q0m"; "/cgi-bin/pprspt?PDBid [[4q0m]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 100: | Line 117: | ||
<text>5b74</text> | <text>5b74</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5b74"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5b74"; "/cgi-bin/pprspt?PDBid [[5b74]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 107: | Line 125: | ||
<text>5k3o</text> | <text>5k3o</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k3o"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k3o"; "/cgi-bin/pprspt?PDBid [[5k3o]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 114: | Line 133: | ||
<text>5k45</text> | <text>5k45</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k45"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k45"; "/cgi-bin/pprspt?PDBid [[5k45]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 121: | Line 141: | ||
<text>5k4g</text> | <text>5k4g</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k4g"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5k4g"; "/cgi-bin/pprspt?PDBid [[5k4g]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 128: | Line 149: | ||
<text>5mq5</text> | <text>5mq5</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5mq5"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5mq5"; "/cgi-bin/pprspt?PDBid [[5mq5]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 135: | Line 157: | ||
<text>5ot0</text> | <text>5ot0</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5ot0"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/5ot0"; "/cgi-bin/pprspt?PDBid [[5ot0]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 142: | Line 165: | ||
<text>6rud</text> | <text>6rud</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6rud"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6rud"; "/cgi-bin/pprspt?PDBid [[6rud]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 149: | Line 173: | ||
<text>6ruf</text> | <text>6ruf</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6ruf"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6ruf"; "/cgi-bin/pprspt?PDBid [[6ruf]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 156: | Line 181: | ||
<text>6syh</text> | <text>6syh</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6syh"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6syh"; "/cgi-bin/pprspt?PDBid [[6syh]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 163: | Line 189: | ||
<text>6uog</text> | <text>6uog</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6uog"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6uog"; "/cgi-bin/pprspt?PDBid [[6uog]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 170: | Line 197: | ||
<text>6v5f</text> | <text>6v5f</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6v5f"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6v5f"; "/cgi-bin/pprspt?PDBid [[6v5f]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 177: | Line 205: | ||
<text>6wz6</text> | <text>6wz6</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6wz6"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/6wz6"; "/cgi-bin/pprspt?PDBid [[6wz6]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 184: | Line 213: | ||
<text>7a0u</text> | <text>7a0u</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7a0u"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7a0u"; "/cgi-bin/pprspt?PDBid [[7a0u]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 191: | Line 221: | ||
<text>7p9c</text> | <text>7p9c</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7p9c"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7p9c"; "/cgi-bin/pprspt?PDBid [[7p9c]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 198: | Line 229: | ||
<text>7r57</text> | <text>7r57</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r57"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r57"; "/cgi-bin/pprspt?PDBid [[7r57]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 205: | Line 237: | ||
<text>7r5q</text> | <text>7r5q</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r5q"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7r5q"; "/cgi-bin/pprspt?PDBid [[7r5q]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 212: | Line 245: | ||
<text>7u6m</text> | <text>7u6m</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7u6m"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/7u6m"; "/cgi-bin/pprspt?PDBid [[7u6m]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 219: | Line 253: | ||
<text>8ecd</text> | <text>8ecd</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8ecd"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8ecd"; "/cgi-bin/pprspt?PDBid [[8ecd]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| Line 226: | Line 261: | ||
<text>8h48</text> | <text>8h48</text> | ||
<script>zap; | <script>zap; | ||
| - | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8h48"; "/cgi-bin/pprspt"; | + | load file "/cgi-bin/pprstr?bc356b44effd36197439439e31c1852b/8h48"; "/cgi-bin/pprspt?PDBid [[8h48]]"; |
| + | |||
</script> | </script> | ||
</item> | </item> | ||
| - | |||
</jmolMenu></jmol> | </jmolMenu></jmol> | ||
Current revision
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