The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia

Yonglan Liu, Hyunbum Jang, Mingzhen Zhang, Chung Jung Tsai, Ryan Maloney, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


BCR-ABL drives chronic myeloid leukemia (CML). BCR binding to GRB2 transduces signaling via the Ras/MAPK pathway. Despite considerable data confirming the binding, molecular-level understanding of exactly how the two proteins interact, and, especially, what are the determinants of the specificity of the SH2GRB2 domain-phosphorylated BCR (pBCR) recognition are still open questions. Yet, this is vastly important for understanding binding selectivity, and for predicting the phosphorylated receptors, or peptides, that are likely to bind. Here, we uncover these determinants and ascertain to what extent they relate to the affinity of the interaction. Toward this end, we modeled the complexes of the pBCR and SH2GRB2 and other pY/Y-peptide-SH2 complexes and compared their specificity and affinity. We observed that pBCR's 176FpYVNV180 motif is favorable and specific to SH2GRB2, similar to pEGFR, but not other complexes. SH2GRB2 contains two binding pockets: pY-binding recognition pocket triggers binding, and the specificity pocket whose interaction is governed by N179 in pBCR and W121 in SH2GRB2. Our proposed motif with optimal affinity to SH2GRB2 is E/D-pY-E/V-N-I/L. Collectively, we provide the structural basis of BCR-ABL recruitment of GRB2, outline its specificity hallmarks, and delineate a blueprint for prediction of BCR-binding scaffolds and for therapeutic peptide design.

Original languageEnglish
Pages (from-to)2251-2265
Number of pages15
JournalBiophysical Journal
Issue number12
StatePublished - 21 Jun 2022


FundersFunder number
National Institutes of HealthHHSN261201500003I
U.S. Department of Health and Human Services
National Cancer InstituteZIABC010441
Government of South Australia


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