6MFQ
Crystal structure of a PMS2 variant
Summary for 6MFQ
| Entry DOI | 10.2210/pdb6mfq/pdb |
| Descriptor | Mismatch repair endonuclease PMS2 (2 entities in total) |
| Functional Keywords | mismatch repair, variant of uncertain significance, atpase domain, hydrolase, dna repair enzyme |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 81997.53 |
| Authors | D'Arcy, B.M.,Prakash, A. (deposition date: 2018-09-11, release date: 2019-02-06, Last modification date: 2023-10-11) |
| Primary citation | D'Arcy, B.M.,Blount, J.,Prakash, A. Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene. Hum. Mutat., 40:458-471, 2019 Cited by PubMed Abstract: Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%-30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In the current study, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42-44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small-angle X-ray scattering, and X-ray crystallography of the N-terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild-type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation. PubMed: 30653781DOI: 10.1002/humu.23708 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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