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4kxz

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crystal structure of tgfb2 in complex with GC2008.

Structural highlights

4kxz is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TGFB2_HUMAN Note=A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9. Defects in TGFB2 are the cause of Loeys-Dietz syndrome 4 (LDS4) [MIM:614816. An aortic aneurysm syndrome with widespread systemic involvement. LDS4 is characterized by arterial tortuosity, aortic dissection, intracranial aneurysm and subarachnoid hemorrhage, hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arachnodactyly, scoliosis, foot deformities, dural ectasia, joint hyperflexibility, and thin skin with easy bruising and striae.^[1]

Function

TGFB2_HUMAN TGF-beta 2 has suppressive effects on interleukin-2 dependent T-cell growth.

Publication Abstract from PubMed

Various important biological pathways are modulated by TGFbeta isoforms; as such they are potential targets for therapeutic intervention. Fresolimumab, also known as GC1008, is a pan-TGFbeta neutralizing antibody that has been tested clinically for several indications including an ongoing trial for focal segmental glomerulosclerosis. The structure of the antigen-binding fragment of fresolimumab (GC1008 Fab) in complex with TGFbeta3 has been reported previously, but the structural capacity of fresolimumab to accommodate tight interactions with TGFbeta1 and TGFbeta2 was insufficiently understood. We report the crystal structure of the single-chain variable fragment of fresolimumab (GC1008 scFv) in complex with target TGFbeta1 to a resolution of 3.00 A and the crystal structure of GC1008 Fab in complex with TGFbeta2 to 2.83 A. The structures provide further insight into the details of TGFbeta recognition by fresolimumab, give a clear indication of the determinants of fresolimumab pan-specificity and provide potential starting points for the development of isoform-specific antibodies using a fresolimumab scaffold.

Structures of a pan-specific antagonist antibody complexed to different isoforms of TGFbeta reveal structural plasticity of antibody-antigen interactions.,Moulin A, Mathieu M, Lawrence C, Bigelow R, Levine M, Hamel C, Marquette JP, Le Parc J, Loux C, Ferrari P, Capdevila C, Dumas J, Dumas B, Rak A, Bird J, Qiu H, Pan CQ, Edmunds T, Wei RR Protein Sci. 2014 Sep 10. doi: 10.1002/pro.2548. PMID:25209176^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012 Jul 8;44(8):922-7. doi: 10.1038/ng.2349. PMID:22772368 doi:10.1038/ng.2349
↑ Moulin A, Mathieu M, Lawrence C, Bigelow R, Levine M, Hamel C, Marquette JP, Le Parc J, Loux C, Ferrari P, Capdevila C, Dumas J, Dumas B, Rak A, Bird J, Qiu H, Pan CQ, Edmunds T, Wei RR. Structures of a pan-specific antagonist antibody complexed to different isoforms of TGFbeta reveal structural plasticity of antibody-antigen interactions. Protein Sci. 2014 Sep 10. doi: 10.1002/pro.2548. PMID:25209176 doi:http://dx.doi.org/10.1002/pro.2548