Database accession: MF7000461
Name: Mouse Glyoxalase I complex
PDB ID: 2za0
Experimental method: X-ray (1.70 Å)
Assembly: Homodimer
Source organism: Mus musculus
Primary publication of the structure:
Kawatani M, Okumura H, Honda K, Kanoh N, Muroi M, Dohmae N, Takami M, Kitagawa M, Futamura Y, Imoto M, Osada H
The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I.
(2008) Proc. Natl. Acad. Sci. U.S.A. 105: 11691-6
PMID: 18695250
Abstract:
Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
lactoylglutathione lyase activity lactoylglutathione lyase activity
zinc ion binding zinc ion binding
Biological process:
glutathione metabolic process glutathione metabolic process
methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione
methylglyoxal metabolic process methylglyoxal metabolic process
negative regulation of apoptotic process negative regulation of apoptotic process
osteoclast differentiation osteoclast differentiation
regulation of transcription by RNA polymerase II regulation of transcription by RNA polymerase II
Cellular component:
cytosol cytosol
nucleoplasm nucleoplasm
plasma membrane plasma membrane
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Lactoylglutathione lyase
Source organism: Mus musculus
Length: 184 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMAEPQPASSGLTDETAFSCCSDPDPSTKDFLLQQTMLRIKDPKKSLDFYTRVLGLTLLQKLDFPAMKFSLYFLAYEDKNDIPKDKSEKTAWTFSRKATLELTHNWGTEDDETQSYHNGNSDPRGFGHIGIAVPDVYSACKRFEELGVKFVKKPDDGKMKGLAFIQDPDGYWIEILNPNKIATII
UniProtKB AC: Q9CPU0 (positions: 4-183)
Coverage: 97%
Name: Lactoylglutathione lyase
Source organism: Mus musculus
Length: 184 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMAEPQPASSGLTDETAFSCCSDPDPSTKDFLLQQTMLRIKDPKKSLDFYTRVLGLTLLQKLDFPAMKFSLYFLAYEDKNDIPKDKSEKTAWTFSRKATLELTHNWGTEDDETQSYHNGNSDPRGFGHIGIAVPDVYSACKRFEELGVKFVKKPDDGKMKGLAFIQDPDGYWIEILNPNKIATII
UniProtKB AC: Q9CPU0 (positions: 9-184)
Coverage: 95%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily
Evidence level: Indirect evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
The VOC superfamily of metalloenzymes is characterized by a three-dimensional domain-swapped arrangement of tandem βαβββ-motifs (PMID:24447055). The original gene duplication event led to the βαβββ tandem structure, which appears to require dimerization for stability. Two different forms of domain-swapped dimers may coexist in solution (PMID:12121648) in which both subunits of the homodimer participate in coordination of each metal ion and formation of the U-shaped active sites in the enzyme (PMID:24004181). The complex is predominantly dimeric in solution (gel filtration) (PMID:12121648).
Chain A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
Download this entry's XML file (.xml)
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