6bcm: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6bcm is ~~ON HOLD until Paper~~ Publication

==Structure of a Self-inhibited N475A variant of the Venezuelan Equine Encephalitis Virus (VEEV) nsP2 cysteine protease==

== Structural highlights ==

<table><tr><td colspan='2'>[[6bcm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BCM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BCM FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=6bcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bcm OCA], [http://pdbe.org/6bcm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bcm RCSB], [http://www.ebi.ac.uk/pdbsum/6bcm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bcm ProSAT]</span></td></tr>

</table>

== Publication Abstract from PubMed ==

The alphaviral nsP2 cysteine protease of the Venezuelan equine encephalitis virus (VEEV) is a validated anti-viral drug target. Clan CN proteases contain a cysteine protease domain that is intimately packed with an S-adenosyl-L-methionine dependent RNA methyltransferase (SAM MTase) domain. Within a cleft formed at the interface of these two domains, the peptide substrate is thought to bind. The nucleophilic cysteine can be found within a conserved motif, 475NVCWAK480, which differs from that of papain (22CGSCWAFS29). Mutation of the motif residue, N475, to alanine unexpectedly produced a self-inhibited state where the N-terminal residues flipped into the substrate-binding cleft. Notably, the N-terminal segment was not hydrolyzed, consistent with a catalytically incompetent state. The N475A mutation resulted in a 70-fold decrease in the kcat/Km. A side-chain to substrate interaction was predicted by the structure; the S701A mutation led to a 17-fold increase in the Km. An Asn at the n-2 position relative to the Cys was also found in the coronaviral papain-like proteases/deubiquitinases (PLpro) of the SARS and MERS viruses, and in several papain-like human ubiquitin specific proteases (USP). The large conformational change in the N475A variant suggests that Asn-475 plays an important role in stabilizing the N-terminal residues and in orienting the carbonyl during nucleophilic attack, but does not directly hydrogen bond the oxyanion. The state trapped in crystallo is an unusual result of site-directed mutagenesis, but reveals the role of this highly conserved Asn and identifies key substrate-binding contacts that may be exploited by peptide-like inhibitors.

~~Authors:~~ Compton, J.R.~~, Legler, P~~.M.

Mutation of Asn-475 in the Venezuelan Equine Encephalitis Virus nsP2 Cysteine Protease leads to a Self-inhibited state.,Compton J, Mickey M, Hu X, Marugan JJ, Legler PM Biochemistry. 2017 Oct 24. doi: 10.1021/acs.biochem.7b00746. PMID:29064679<ref>PMID:29064679</ref>

~~Description: Structure of~~ a ~~Self-inhibited N475A variant~~ of the ~~Venezuelan Equine Encephalitis Virus (VEEV) nsP2 cysteine protease~~

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

~~[[Category~~: ~~Unreleased Structures]]~~

</div>

[[Category: Compton, J.R]]

[[Category: Legler, P.M]]

== References ==

__TOC__

</StructureSection>

[[Category: Compton, J R]]

[[Category: Legler, P M]]

[[Category: Alphavirus]]

[[Category: Cysteine protease]]

[[Category: N475a]]

[[Category: Nonstructural protein]]

[[Category: Nsp2]]

[[Category: S-adenosyl-l-methionine methyltransferase]]

[[Category: Self-inhibited]]

[[Category: Viral protein]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6bcm is ON HOLD  until Paper Publication
+==Structure of a Self-inhibited N475A variant of the Venezuelan Equine Encephalitis Virus (VEEV) nsP2 cysteine protease==
+<StructureSection load='6bcm' size='340' side='right' caption='[[6bcm]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6bcm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BCM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BCM FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=6bcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bcm OCA], [http://pdbe.org/6bcm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bcm RCSB], [http://www.ebi.ac.uk/pdbsum/6bcm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bcm ProSAT]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The alphaviral nsP2 cysteine protease of the Venezuelan equine encephalitis virus (VEEV) is a validated anti-viral drug target. Clan CN proteases contain a cysteine protease domain that is intimately packed with an S-adenosyl-L-methionine dependent RNA methyltransferase (SAM MTase) domain. Within a cleft formed at the interface of these two domains, the peptide substrate is thought to bind. The nucleophilic cysteine can be found within a conserved motif, 475NVCWAK480, which differs from that of papain (22CGSCWAFS29). Mutation of the motif residue, N475, to alanine unexpectedly produced a self-inhibited state where the N-terminal residues flipped into the substrate-binding cleft. Notably, the N-terminal segment was not hydrolyzed, consistent with a catalytically incompetent state. The N475A mutation resulted in a 70-fold decrease in the kcat/Km. A side-chain to substrate interaction was predicted by the structure; the S701A mutation led to a 17-fold increase in the Km. An Asn at the n-2 position relative to the Cys was also found in the coronaviral papain-like proteases/deubiquitinases (PLpro) of the SARS and MERS viruses, and in several papain-like human ubiquitin specific proteases (USP). The large conformational change in the N475A variant suggests that Asn-475 plays an important role in stabilizing the N-terminal residues and in orienting the carbonyl during nucleophilic attack, but does not directly hydrogen bond the oxyanion. The state trapped in crystallo is an unusual result of site-directed mutagenesis, but reveals the role of this highly conserved Asn and identifies key substrate-binding contacts that may be exploited by peptide-like inhibitors.
-Authors: Compton, J.R., Legler, P.M.
+Mutation of Asn-475 in the Venezuelan Equine Encephalitis Virus nsP2 Cysteine Protease leads to a Self-inhibited state.,Compton J, Mickey M, Hu X, Marugan JJ, Legler PM Biochemistry. 2017 Oct 24. doi: 10.1021/acs.biochem.7b00746. PMID:29064679<ref>PMID:29064679</ref>
-Description: Structure of a Self-inhibited N475A variant of the Venezuelan Equine Encephalitis Virus (VEEV) nsP2 cysteine protease
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Compton, J.R]]
+<div class="pdbe-citations 6bcm" style="background-color:#fffaf0;"></div>
-[[Category: Legler, P.M]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Compton, J R]]
+[[Category: Legler, P M]]
+[[Category: Alphavirus]]
+[[Category: Cysteine protease]]
+[[Category: N475a]]
+[[Category: Nonstructural protein]]
+[[Category: Nsp2]]
+[[Category: S-adenosyl-l-methionine methyltransferase]]
+[[Category: Self-inhibited]]
+[[Category: Viral protein]]