5dj0: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
The | ==Fc Heterodimer Design 11.2 Y349S/K370Y + E357D/S364Q== | ||
<StructureSection load='5dj0' size='340' side='right' caption='[[5dj0]], [[Resolution|resolution]] 2.28Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5dj0]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DJ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DJ0 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5di8|5di8]], [[5dj2|5dj2]], [[5dj6|5dj6]], [[5dj8|5dj8]], [[5dja|5dja]], [[5djc|5djc]], [[5djd|5djd]], [[5djx|5djx]], [[5djy|5djy]], [[5djz|5djz]], [[5dk0|5dk0]], [[5dk2|5dk2]], [[5dvk|5dvk]], [[5dvl|5dvl]], [[5dvm|5dvm]], [[5dvn|5dvn]], [[5dvo|5dvo]]</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=5dj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dj0 OCA], [http://pdbe.org/5dj0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dj0 RCSB], [http://www.ebi.ac.uk/pdbsum/5dj0 PDBsum]</span></td></tr> | |||
</table> | |||
== 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A challenge in the structure-based design of specificity is modeling the negative states, i.e., the complexes that you do not want to form. This is a difficult problem because mutations predicted to destabilize the negative state might be accommodated by small conformational rearrangements. To overcome this challenge, we employ an iterative strategy that cycles between sequence design and protein docking in order to build up an ensemble of alternative negative state conformations for use in specificity prediction. We have applied our technique to the design of heterodimeric CH3 interfaces in the Fc region of antibodies. Combining computationally and rationally designed mutations produced unique designs with heterodimer purities greater than 90%. Asymmetric Fc crystallization was able to resolve the interface mutations; the heterodimer structures confirmed that the interfaces formed as designed. With these CH3 mutations, and those made at the heavy-/light-chain interface, we demonstrate one-step synthesis of four fully IgG-bispecific antibodies. | |||
Computationally Designed Bispecific Antibodies using Negative State Repertoires.,Leaver-Fay A, Froning KJ, Atwell S, Aldaz H, Pustilnik A, Lu F, Huang F, Yuan R, Hassanali S, Chamberlain AK, Fitchett JR, Demarest SJ, Kuhlman B Structure. 2016 Apr 5;24(4):641-51. doi: 10.1016/j.str.2016.02.013. Epub 2016 Mar, 17. PMID:26996964<ref>PMID:26996964</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5dj0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aldaz, H]] | [[Category: Aldaz, H]] | ||
[[Category: Atwell, S]] | |||
[[Category: Chamberlain, A K]] | |||
[[Category: Demarest, S J]] | |||
[[Category: Dhanani, S H]] | |||
[[Category: Fitchett, J R]] | |||
[[Category: Froning, K J]] | |||
[[Category: Gutierrez, B]] | [[Category: Gutierrez, B]] | ||
[[Category: | [[Category: Hendle, J]] | ||
[[Category: | [[Category: Huang, F]] | ||
[[Category: Kuhlman, B]] | [[Category: Kuhlman, B]] | ||
[[Category: | [[Category: Leaver-Fay, A]] | ||
[[Category: Lu, F]] | [[Category: Lu, F]] | ||
[[Category: Pustilnik, A]] | [[Category: Pustilnik, A]] | ||
[[Category: Yuan, R]] | |||
[[Category: Bispecific antibody]] | |||
[[Category: Ch3]] | |||
[[Category: Fc]] | |||
[[Category: Heterodimer]] | |||
[[Category: Immune system]] | |||
[[Category: Immunoglobulin]] | |||
Revision as of 20:27, 10 May 2016
Fc Heterodimer Design 11.2 Y349S/K370Y + E357D/S364QFc Heterodimer Design 11.2 Y349S/K370Y + E357D/S364Q
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. Publication Abstract from PubMedA challenge in the structure-based design of specificity is modeling the negative states, i.e., the complexes that you do not want to form. This is a difficult problem because mutations predicted to destabilize the negative state might be accommodated by small conformational rearrangements. To overcome this challenge, we employ an iterative strategy that cycles between sequence design and protein docking in order to build up an ensemble of alternative negative state conformations for use in specificity prediction. We have applied our technique to the design of heterodimeric CH3 interfaces in the Fc region of antibodies. Combining computationally and rationally designed mutations produced unique designs with heterodimer purities greater than 90%. Asymmetric Fc crystallization was able to resolve the interface mutations; the heterodimer structures confirmed that the interfaces formed as designed. With these CH3 mutations, and those made at the heavy-/light-chain interface, we demonstrate one-step synthesis of four fully IgG-bispecific antibodies. Computationally Designed Bispecific Antibodies using Negative State Repertoires.,Leaver-Fay A, Froning KJ, Atwell S, Aldaz H, Pustilnik A, Lu F, Huang F, Yuan R, Hassanali S, Chamberlain AK, Fitchett JR, Demarest SJ, Kuhlman B Structure. 2016 Apr 5;24(4):641-51. doi: 10.1016/j.str.2016.02.013. Epub 2016 Mar, 17. PMID:26996964[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||