1kc2: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1kc2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rous_sarcoma_virus Rous sarcoma virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KC2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1kc2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rous_sarcoma_virus Rous sarcoma virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KC2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Transferase Transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></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=1kc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kc2 OCA], [https://pdbe.org/1kc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1kc2 RCSB], [https://www.ebi.ac.uk/pdbsum/1kc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1kc2 ProSAT]</span></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=1kc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kc2 OCA], [https://pdbe.org/1kc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1kc2 RCSB], [https://www.ebi.ac.uk/pdbsum/1kc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1kc2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/SRC_RSVSA SRC_RSVSA]] This phosphoprotein, required for both the initiation and the maintenance of neoplastic transformation, is a protein kinase that catalyzes the phosphorylation of tyrosine residues in vitro.  
[https://www.uniprot.org/uniprot/SRC_RSVSA SRC_RSVSA] This phosphoprotein, required for both the initiation and the maintenance of neoplastic transformation, is a protein kinase that catalyzes the phosphorylation of tyrosine residues in vitro.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</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=1kc2 ConSurf].
</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=1kc2 ConSurf].
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<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Src Homology (SH2) domains play critical roles in signaling pathways by binding to phosphotyrosine (pTyr)-containing sequences, thereby recruiting SH2 domain-containing proteins to tyrosine-phosphorylated sites on receptor molecules. Investigations of the peptide binding specificity of the SH2 domain of the Src kinase (Src SH2 domain) have defined the EEI motif C-terminal to the phosphotyrosine as the preferential binding sequence. A subsequent study that probed the importance of eight specificity-determining residues of the Src SH2 domain found two residues which when mutated to Ala had significant effects on binding: Tyr beta D5 and Lys beta D3. The mutation of Lys beta D3 to Ala was particularly intriguing, since a Glu to Ala mutation at the first (+1) position of the EEI motif (the residue interacting with Lys beta D3) did not significantly affect binding. Hence, the interaction between Lys beta D3 and +1 Glu is energetically coupled. This study is focused on the dissection of the energetic coupling observed across the SH2 domain-phosphopeptide interface at and around the +1 position of the peptide. It was found that three residues of the SH2 domain, Lys beta D3, Asp beta C8 and AspCD2 (altogether forming the so-called +1 binding region) contribute to the selection of Glu at the +1 position of the ligand. A double (Asp beta C8Ala, AspCD2Ala) mutant does not exhibit energetic coupling between Lys beta D3 and +1 Glu, and binds to the pYEEI sequence 0.3 kcal/mol tighter than the wild-type Src SH2 domain. These results suggest that Lys beta D3 in the double mutant is now free to interact with the +1 Glu and that the role of Lys beta D3 in the wild-type is to neutralize the acidic patch formed by Asp beta C8 and AspCD2 rather than specifically select for a Glu at the +1 position as it had been hypothesized previously. A triple mutant (Lys beta D3Ala, Asp beta C8Ala, AspCD2Ala) has reduced binding affinity compared to the double (Asp beta C8Ala, AspCD2Ala) mutant, yet binds the pYEEI peptide as well as the wild-type Src SH2 domain. The structural basis for such high affinity interaction was investigated crystallographically by determining the structure of the triple (Lys beta D3Ala, Asp beta C8Ala, AspCD2Ala) mutant bound to the octapeptide PQpYEEIPI (where pY indicates a phosphotyrosine). This structure reveals for the first time contacts between the SH2 domain and the -1 and -2 positions of the peptide (i.e. the two residues N-terminal to pY). Thus, unexpectedly, mutations in the +1 binding region affect binding of other regions of the peptide. Such additional contacts may account for the high affinity interaction of the triple mutant for the pYEEI-containing peptide.
Dissection of the energetic coupling across the Src SH2 domain-tyrosyl phosphopeptide interface.,Lubman OY, Waksman G J Mol Biol. 2002 Feb 15;316(2):291-304. PMID:11851339<ref>PMID:11851339</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1kc2" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Rous sarcoma virus]]
[[Category: Rous sarcoma virus]]
[[Category: Transferase]]
[[Category: Lubman OY]]
[[Category: Lubman, O Y]]
[[Category: Waksman G]]
[[Category: Waksman, G]]
[[Category: Phosphotyrosine]]
[[Category: Sh2 domain]]

Revision as of 07:59, 3 April 2024

structure of the triple (Lys(beta)D3Ala, Asp(beta)C8Ala, AspCD2Ala) mutant of the Src SH2 domain bound to the PQpYEEIPI peptide

1kc2, resolution 2.10Å

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