ISDA: 9ZPA

Deposition Date 2025-12-16

Release Date 2026-06-03

Last Version Date 2026-06-03

Entry Detail

PDB ID:

9ZPA

Keywords:

ONCOPROTEIN

Title:

KRAS G12V Mutant in Complex with GDP and Compound 12.

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

1.68 Å

R-Value Free:

0.25

R-Value Work:

0.22

R-Value Observed:

0.22

Space Group:

P 1 21 1

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Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:Isoform 2B of GTPase KRas
Gene (Uniprot):KRAS
Mutagens:G12V, C51S, C80L, C118S
Chain IDs:A, B
Chain Length:171
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:P01116 Pfam ID:PF00071 EC:3.6.5.2

Ligand Molecules

A1C3N

GDP

SO4

Primary Citation

Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation.

Phillips, D.P, Alper, P.B, Cho, C.Y, Borkin, D, Han, D, Kochanek, S.E, Vidal-Biggart, A, Herath, A, Gurjar, J, Lu, W, Mathison, C.J.N, Nelson, J.M, Pei, W, Yan, S, Nguyen, B.N, Hoffman, T, Okram, B, Nguyen, T.N, Jiang, S, Masick, B.T, Wang, Z, Nikulin, V, Yin, H, Chen, Y, Juarez, J, Sarkisova, Y, Jia, Y, Zhou, V, Liu, G, Liu, X, Lu, M, Taylor, B.L, Huynh, L, Wang, Y, Pacoma, R, Baaten, J, Topolewski, K, Wright, C, Nguyen, T, Knee, D.A, Liu, Q, Liu, J, Li, J, Virata, C, Briones, S, DiDonato, M, Bursulaya, B, Jones, D.H, Witmer, D, Chu, C, Jin, H, Richmond, W, Westling, L, Hollenbeck, T, Chong, A, Franey, S, Groessl, T, Shapiro, M, Effenberger, K, Arroyo, K, Bretz, A, Honda, A, Brown, J, Sanchez, C.C, Gordon, W.P, Matzen, J.T, Osterman, N, Cotesta, S, Brachmann, S.M, Wilcken, R, Zecri, F, Beyer, K.S, Molteni, V, Haling, J.R.Show

J.Med.Chem. ? ? ? (2026)

PMID: 42155964 DOI: 10.1021/acs.jmedchem.6c00127

Abstact

The RAS Switch-II pockets' discovery enabled targeting a challenging molecular site. Covalent KRAS(G12C) inhibitors inspired efforts to find compounds for other KRAS mutations, notably KRAS(G12D) and KRAS(G12V). A macrocyclization strategy led to the identification of an exceptionally potent lead compound 12. Highly optimized interactions in the pocket yielded strong affinity against KRAS(G12D) and KRAS(G12V), potent inhibition of phospho-ERK in various KRAS mutant cell lines, and tumor regression in mouse xenograft models.

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Protein

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Disease

Primary Citation of related structures

Abstact

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