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| | ==Knob-into-hole IgG Fc== | | ==Knob-into-hole IgG Fc== |
| - | <StructureSection load='4nqs' size='340' side='right' caption='[[4nqs]], [[Resolution|resolution]] 2.64Å' scene=''> | + | <StructureSection load='4nqs' size='340' side='right'caption='[[4nqs]], [[Resolution|resolution]] 2.64Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nqs]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NQS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NQS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nqs]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Staphylococcus Staphylococcus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NQS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NQS FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nqt|4nqt]], [[4nqu|4nqu]]</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]] 2.64Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IGHG1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4nqs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nqs OCA], [https://pdbe.org/4nqs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nqs RCSB], [https://www.ebi.ac.uk/pdbsum/4nqs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nqs ProSAT]</span></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=4nqs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nqs OCA], [http://pdbe.org/4nqs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nqs RCSB], [http://www.ebi.ac.uk/pdbsum/4nqs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nqs ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/IGHG1_HUMAN IGHG1_HUMAN]] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:[http://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. | + | [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] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Eigenbrot, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Ultsch, M]] | + | [[Category: Staphylococcus]] |
| - | [[Category: Immune system]] | + | [[Category: Eigenbrot C]] |
| - | [[Category: Immunoglobulin]] | + | [[Category: Ultsch M]] |
| Structural highlights
Disease
IGHG1_HUMAN Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM: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
IGHG1_HUMAN
Publication Abstract from PubMed
Bispecific antibody and antibody-like molecules are of wide interest as potential therapeutics that can recognize two distinct targets. Among the variety of ways such molecules have been engineered is by creating "knob" and "hole" heterodimerization sites in the CH3 domains of two antibody heavy chains. The molecules produced in this manner maintain their biological activities while differing very little from the native human IgG sequence. To better understand the knob-into-hole interface, the molecular mechanism of heterodimerization, and to engineer Fc domains that could improve the assembly and purity of heterodimeric reaction products, we sought crystal structures of aglycosylated heterodimeric and homodimeric "knob" and "hole" Fc fragments derived from bacterial expression. The structure of the knob-into-hole Fc was determined at 2.64A. Except for the sites of mutation, the structure is very similar to that of the native human IgG1 Fc, consistent with a heterodimer interaction kinetic KD of <1nM. Homodimers of the "knob" and "hole" mutants were also obtained, and their X-ray structures were determined at resolutions 2.5A and 2.1A, respectively. Both kinds of homodimers adopt a head-to-tail quaternary structure and thus do not contain direct knob/knob or hole/hole CH3 interactions. The head-to-tail arrangement was disfavored by adding site-directed mutations at F241 and F243 in the CH2 domains, leading to increases in both rate and efficiency of bispecific (heterodimer) assembly.
Antiparallel Conformation of Knob and Hole Aglycosylated Half-Antibody Homodimers Is Mediated by a CH2-CH3 Hydrophobic Interaction.,Michael Elliott J, Ultsch M, Lee J, Tong R, Takeda K, Spiess C, Eigenbrot C, Scheer JM J Mol Biol. 2014 Feb 24. pii: S0022-2836(14)00097-7. doi:, 10.1016/j.jmb.2014.02.015. PMID:24576605[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Michael Elliott J, Ultsch M, Lee J, Tong R, Takeda K, Spiess C, Eigenbrot C, Scheer JM. Antiparallel Conformation of Knob and Hole Aglycosylated Half-Antibody Homodimers Is Mediated by a CH2-CH3 Hydrophobic Interaction. J Mol Biol. 2014 Feb 24. pii: S0022-2836(14)00097-7. doi:, 10.1016/j.jmb.2014.02.015. PMID:24576605 doi:http://dx.doi.org/10.1016/j.jmb.2014.02.015
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