PDBsum entry 6e6c

Signaling protein

PDB id: 6e6c

Contents

Protein chain

164 a.a.

Ligands

GNP

Metals

_CA

_MG

Waters ×85

PDB id:

6e6c

Name:

Signaling protein

Title:

Hras g13d bound to gppnhp (h13gnp)

Structure:

Gtpase hras. Chain: a. Fragment: residues 1-166. Synonym: h-ras-1,ha-ras,transforming protein p21,c-h-ras,p21ras. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.90Å R-factor: 0.168 R-free: 0.230

Authors:

C.W.Johnson,C.Mattos

Key ref:

C.W.Johnson et al. (2019). Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D. Cell Rep, 28, 1538. PubMed id: 31390567 DOI: 10.1016/j.celrep.2019.07.026

Date:

24-Jul-18 Release date: 31-Jul-19

Protein chain

P01112  (RASH_HUMAN) -  GTPase HRas from Homo sapiens

Seq: 189 a.a.

Struc: 164 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GNP) matches with 81.82% similarity) + phosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.celrep.2019.07.026

Cell Rep 28:1538 (2019)

PubMed id: 31390567

Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.

C.W.Johnson, Y.J.Lin, D.Reid, J.Parker, S.Pavlopoulos, P.Dischinger, C.Graveel, A.J.Aguirre, M.Steensma, K.M.Haigis, C.Mattos.

ABSTRACT

Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A59 is placed in the Mg²⁺ binding site, as in the HRas-SOS complex. Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part the elevated frequency of the G13D mutant in KRas over the other isoforms of Ras.