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[[Image:1d6v.gif|left|200px]]
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{{STRUCTURE_1d6v|  PDB=1d6v  |  SCENE=  }}
'''CONFORMATION EFFECTS IN BIOLOGICAL CATALYSIS INTRODUCED BY OXY-COPE ANTIBODY MATURATION'''


==CONFORMATION EFFECTS IN BIOLOGICAL CATALYSIS INTRODUCED BY OXY-COPE ANTIBODY MATURATION==
<StructureSection load='1d6v' size='340' side='right'caption='[[1d6v]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1d6v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D6V FirstGlance]. <br>
</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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=HOP:(1S,2S,5S)2-(4-GLUTARIDYLBENZYL)-5-PHENYL-1-CYCLOHEXANOL'>HOP</scene></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=1d6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d6v OCA], [https://pdbe.org/1d6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d6v RCSB], [https://www.ebi.ac.uk/pdbsum/1d6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d6v ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/IGHG1_HUMAN IGHG1_HUMAN] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:[https://omim.org/entry/254500 254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4.
== Function ==
[https://www.uniprot.org/uniprot/IGHG1_HUMAN IGHG1_HUMAN]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d6/1d6v_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=1d6v ConSurf].
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Antibody AZ-28 was generated against the chairlike transition-state analogue (TSA) 1 and catalyzes the oxy-Cope rearrangement of substrate 2 to product 3. The germline precursor to AZ-28 catalyzes the reaction with a 35-fold higher rate (k(cat)/k(uncat) = 163 000), despite a 40-fold lower binding affinity for TSA.1 (K(D) = 670 nM). To determine the structural basis for the differences in the binding and catalytic properties of the germline and affinity-matured antibodies, the X-ray crystal structures of the unliganded and TSA.1 complex of antibody AZ-28 have been determined at 2.8 and 2.6 A resolution, respectively; the structures of the unliganded and TSA.1 complex of the germline precursor to AZ-28 were both determined at 2. 0 A resolution. In the affinity-matured antibody.hapten complex the TSA is fixed in a catalytically unfavorable conformation by a combination of van der Waals and hydrogen-bonding interactions. The 2- and 5-phenyl substituents of TSA.1 are almost perpendicular to the cyclohexyl ring, leading to decreased orbital overlap and decreased stabilization of the putative transition state. The active site of the germline antibody appears to have an increased degree of flexibility-CDRH3 moves 4.9 A outward from the active site upon binding of TSA.1. We suggest that this conformational flexibility in the germline antibody, which results in a lower binding affinity for TSA.1, allows dynamic changes in the dihedral angle of the 2-phenyl substituent along the reaction coordinate. These conformational changes in turn lead to enhanced orbital overlap and increased catalytic rate. These studies suggest that protein and substrate dynamics play a key role in this antibody-catalyzed reaction.


==Overview==
Conformational effects in biological catalysis: an antibody-catalyzed oxy-cope rearrangement.,Mundorff EC, Hanson MA, Varvak A, Ulrich H, Schultz PG, Stevens RC Biochemistry. 2000 Feb 1;39(4):627-32. PMID:10651626<ref>PMID:10651626</ref>
Antibody AZ-28 was generated against the chairlike transition-state analogue (TSA) 1 and catalyzes the oxy-Cope rearrangement of substrate 2 to product 3. The germline precursor to AZ-28 catalyzes the reaction with a 35-fold higher rate (k(cat)/k(uncat) = 163 000), despite a 40-fold lower binding affinity for TSA.1 (K(D) = 670 nM). To determine the structural basis for the differences in the binding and catalytic properties of the germline and affinity-matured antibodies, the X-ray crystal structures of the unliganded and TSA.1 complex of antibody AZ-28 have been determined at 2.8 and 2.6 A resolution, respectively; the structures of the unliganded and TSA.1 complex of the germline precursor to AZ-28 were both determined at 2. 0 A resolution. In the affinity-matured antibody.hapten complex the TSA is fixed in a catalytically unfavorable conformation by a combination of van der Waals and hydrogen-bonding interactions. The 2- and 5-phenyl substituents of TSA.1 are almost perpendicular to the cyclohexyl ring, leading to decreased orbital overlap and decreased stabilization of the putative transition state. The active site of the germline antibody appears to have an increased degree of flexibility-CDRH3 moves 4.9 A outward from the active site upon binding of TSA.1. We suggest that this conformational flexibility in the germline antibody, which results in a lower binding affinity for TSA.1, allows dynamic changes in the dihedral angle of the 2-phenyl substituent along the reaction coordinate. These conformational changes in turn lead to enhanced orbital overlap and increased catalytic rate. These studies suggest that protein and substrate dynamics play a key role in this antibody-catalyzed reaction.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1D6V is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus_and_homo_sapiens Mus musculus and homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D6V OCA].
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<div class="pdbe-citations 1d6v" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Conformational effects in biological catalysis: an antibody-catalyzed oxy-cope rearrangement., Mundorff EC, Hanson MA, Varvak A, Ulrich H, Schultz PG, Stevens RC, Biochemistry. 2000 Feb 1;39(4):627-32. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10651626 10651626]
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
[[Category: Mus musculus and homo sapiens]]
== References ==
[[Category: Protein complex]]
<references/>
[[Category: Hanson, M A.]]
__TOC__
[[Category: Mundorff, E C.]]
</StructureSection>
[[Category: Schultz, P G.]]
[[Category: Homo sapiens]]
[[Category: Stevens, R C.]]
[[Category: Large Structures]]
[[Category: Immune system]]
[[Category: Mus musculus]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 13:31:04 2008''
[[Category: Hanson MA]]
[[Category: Mundorff EC]]
[[Category: Schultz PG]]
[[Category: Stevens RC]]

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