3u7y

From Proteopedia

Structure of NIH45-46 Fab in complex with gp120 of 93TH057 HIV

Structural highlights

3u7y is a 3 chain structure with sequence from Homo sapiens and Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4478Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in CDRH3 contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain/bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.

Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design.,Diskin R, Scheid JF, Marcovecchio PM, West AP Jr, Klein F, Gao H, Gnanapragasam PN, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ Science. 2011 Oct 27. PMID:22033520^[1]

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

References

↑ Diskin R, Scheid JF, Marcovecchio PM, West AP Jr, Klein F, Gao H, Gnanapragasam PN, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ. Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science. 2011 Oct 27. PMID:22033520 doi:10.1126/science.1213782