|
|
| (7 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | {{Seed}} | |
| - | [[Image:3n8m.jpg|left|200px]] | |
| | | | |
| - | <!-- | + | ==Crystal Structure of the Grb2 SH2 Domain in Complex with An Acyclic Ligand Having the Sequence pYVNVP== |
| - | The line below this paragraph, containing "STRUCTURE_3n8m", creates the "Structure Box" on the page.
| + | <StructureSection load='3n8m' size='340' side='right'caption='[[3n8m]], [[Resolution|resolution]] 2.00Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3n8m]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N8M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N8M FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6NA:HEXANOIC+ACID'>6NA</scene>, <scene name='pdbligand=9PR:N-METHYL-L-PROLINAMIDE'>9PR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | {{STRUCTURE_3n8m| PDB=3n8m | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3n8m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n8m OCA], [https://pdbe.org/3n8m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n8m RCSB], [https://www.ebi.ac.uk/pdbsum/3n8m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n8m ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/GRB2_HUMAN GRB2_HUMAN] Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref> Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically-active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and x-ray crystallography. 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls; however, preorganization did not necessarily eventuate in a more favorable binding entropy. Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the linking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein-ligand contacts that might account for the less favorable binding enthalpy of 7; however, an intramolecular hydrogen bond between the pY and pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein-ligand interactions. |
| | | | |
| - | ===Crystal Structure of the Grb2 SH2 Domain in Complex with An Acyclic Ligand Having the Sequence pYVNVP===
| + | Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions.,Delorbe JE, Clements JH, Whiddon BB, Martin SF ACS Med Chem Lett. 2010 Nov 11;1(8):448-452. PMID:21116482<ref>PMID:21116482</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 3n8m" style="background-color:#fffaf0;"></div> |
| | | | |
| - | <!--
| + | ==See Also== |
| - | The line below this paragraph, {{ABSTRACT_PUBMED_21116482}}, adds the Publication Abstract to the page
| + | *[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]] |
| - | (as it appears on PubMed at http://www.pubmed.gov), where 21116482 is the PubMed ID number.
| + | == References == |
| - | -->
| + | <references/> |
| - | {{ABSTRACT_PUBMED_21116482}}
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==About this Structure== | + | |
| - | 3N8M is a 2 chains structure with sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N8M OCA].
| + | |
| - | | + | |
| - | ==Reference== | + | |
| - | <ref group="xtra">PMID:21116482</ref><references group="xtra"/> | + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Clements, J H.]] | + | [[Category: Large Structures]] |
| - | [[Category: Martin, S F.]] | + | [[Category: Clements JH]] |
| - | [[Category: Whiddon, B B.]] | + | [[Category: Martin SF]] |
| - | [[Category: Grb2 sh2 domain]] | + | [[Category: Whiddon BB]] |
| - | [[Category: Ligand preorganization]]
| + | |
| - | [[Category: Macrocycle]]
| + | |
| - | [[Category: Macrocyclic ligand]]
| + | |
| - | [[Category: Protein binding-peptide complex]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec 15 08:41:53 2010''
| + | |
| Structural highlights
Function
GRB2_HUMAN Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.[1] [2] [3] Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.[4] [5] [6]
Publication Abstract from PubMed
The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically-active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and x-ray crystallography. 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls; however, preorganization did not necessarily eventuate in a more favorable binding entropy. Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the linking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein-ligand contacts that might account for the less favorable binding enthalpy of 7; however, an intramolecular hydrogen bond between the pY and pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein-ligand interactions.
Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions.,Delorbe JE, Clements JH, Whiddon BB, Martin SF ACS Med Chem Lett. 2010 Nov 11;1(8):448-452. PMID:21116482[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
- ↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
- ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
- ↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
- ↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
- ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
- ↑ Delorbe JE, Clements JH, Whiddon BB, Martin SF. Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions. ACS Med Chem Lett. 2010 Nov 11;1(8):448-452. PMID:21116482 doi:10.1021/ml100142y
|
