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Titolo:
STRUCTURAL CONSEQUENCES OF HUMANIZING AN ANTIBODY
Autore:
HOLMES MA; FOOTE J;
Indirizzi:
FRED HUTCHINSON CANC RES CTR,DIV MOL MED,1124 COLUMBIA ST C3-168 SEATTLE WA 98104 FRED HUTCHINSON CANC RES CTR,DIV MOL MED SEATTLE WA 98104 UNIV WASHINGTON,DEPT IMMUNOL SEATTLE WA 98195
Titolo Testata:
The Journal of immunology
fascicolo: 5, volume: 158, anno: 1997,
pagine: 2192 - 2201
SICI:
0022-1767(1997)158:5<2192:SCOHAA>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
X-RAY STRUCTURES; RESHAPING HUMAN-ANTIBODIES; ANTIGEN-BINDING DOMAINS; 3-DIMENSIONAL STRUCTURE; MONOCLONAL-ANTIBODY; FRAMEWORK RESIDUES; VARIABLE DOMAINS; ANTI-P185HER2 ANTIBODY; HUMAN-IMMUNOGLOBULIN; HYPERVARIABLE LOOPS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
63
Recensione:
Indirizzi per estratti:
Citazione:
M.A. Holmes e J. Foote, "STRUCTURAL CONSEQUENCES OF HUMANIZING AN ANTIBODY", The Journal of immunology, 158(5), 1997, pp. 2192-2201

Abstract

We have determined the crystal structure of the Fv fragment of a humanized anti-hen eggwhite lysozyme Ab (HuLys). This molecule is a composite of known structures: complementarity-determining regions (CDRs) were from the mouse anti-lysozyme Ab D1.3, heavy chain framework regionswere from the human myeloma protein NEW, and the light chain framework regions were consensus sequences similar to the Bence Jones protein REI. HuLys crystallized in space group P4(3)2(1)2, with two Fv molecules in the crystallographic asymmetric unit. The structure was solved by molecular replacement, using a composite of the parent structures asa search model. The resolution of the structure was 2.87 Angstrom, with an R factor of 22%. There were several unanticipated structural similarities and differences between HuLys and the mouse and human structures. The framework regions of HuLys were as close or closer in conformation to D1.3 than to the NEW or REI protein, despite overwhelming sequence identity with the human framework regions. The effect was most pronounced at the CDR-framework junction, showing that the CDRs can induce structural changes in framework residues, having the net effect in HuLys of reconforming the framework into a conformation more like D1.3. In the combining site, the grafted CDRs retained conformational equilibria seen in D1.3, demonstrating that humanizing can be applied toAbs that bind Ags through isomeric equilibrium or induced fit mechanisms. In addition, HuLys showed systematic differences from D1.3 that resembled domain rotations reported for other Abs. However, the V-H-V-Linterface itself was unaffected, and the apparent movement was actually caused by rearrangements distant from this surface.

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Documento generato il 25/09/20 alle ore 00:31:11