PMID- 32395997
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20231111
IS  - 1549-960X (Electronic)
IS  - 1549-9596 (Print)
IS  - 1549-9596 (Linking)
VI  - 60
IP  - 6
DP  - 2020 Jun 22
TI  - Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 
      2 Domain of the SHP2 Phosphatase.
PG  - 3157-3171
LID - 10.1021/acs.jcim.0c00307 [doi]
AB  - SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a 
      fundamental role in the modulation of several signaling pathways. Germline and 
      somatic mutations in PTPN11 are associated with different rare diseases and 
      hematologic malignancies, and recent studies have individuated SHP2 as a central 
      node in oncogenesis and cancer drug resistance. The SHP2 structure includes two 
      Src homology 2 domains (N-SH2 and C-SH2) followed by a catalytic protein tyrosine 
      phosphatase (PTP) domain. Under basal conditions, the N-SH2 domain blocks the 
      active site, inhibiting phosphatase activity. Association of the N-SH2 domain 
      with binding partners containing short amino acid motifs comprising a 
      phosphotyrosine residue (pY) leads to N-SH2/PTP dissociation and SHP2 activation. 
      Considering the relevance of SHP2 in signaling and disease and the central role 
      of the N-SH2 domain in its allosteric regulation mechanism, we performed 
      microsecond-long molecular dynamics (MD) simulations of the N-SH2 domain 
      complexed to 12 different peptides to define the structural and dynamical 
      features determining the binding affinity and specificity of the domain. 
      Phosphopeptide residues at position -2 to +5, with respect to pY, have 
      significant interactions with the SH2 domain. In addition to the strong 
      interaction of the pY residue with its conserved binding pocket, the complex is 
      stabilized hydrophobically by insertion of residues +1, +3, and +5 in an apolar 
      groove of the domain and interaction of residue -2 with both the pY and a protein 
      surface residue. Additional interactions are provided by hydrogen bonds formed by 
      the backbone of residues -1, +1, +2, and +4. Finally, negatively charged residues 
      at positions +2 and +4 are involved in electrostatic interactions with two 
      lysines (Lys89 and Lys91) specific for the SHP2 N-SH2 domain. Interestingly, the 
      MD simulations illustrated a previously undescribed conformational flexibility of 
      the domain, involving the core beta sheet and the loop that closes the pY binding 
      pocket.
FAU - Anselmi, Massimiliano
AU  - Anselmi M
AUID- ORCID: 0000-0001-5711-770X
AD  - Department of Chemical Science and Technologies, University of Rome Tor Vergata, 
      00133, Rome, Italy.
FAU - Calligari, Paolo
AU  - Calligari P
AD  - Department of Chemical Science and Technologies, University of Rome Tor Vergata, 
      00133, Rome, Italy.
FAU - Hub, Jochen S
AU  - Hub JS
AUID- ORCID: 0000-0001-7716-1767
AD  - Theoretical Physics and Center for Biophysics, Saarland University, Campus E2 6, 
      66123 Saarbrucken, Germany.
FAU - Tartaglia, Marco
AU  - Tartaglia M
AD  - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesu, 
      IRCCS, 00146 Rome, Italy.
FAU - Bocchinfuso, Gianfranco
AU  - Bocchinfuso G
AD  - Department of Chemical Science and Technologies, University of Rome Tor Vergata, 
      00133, Rome, Italy.
FAU - Stella, Lorenzo
AU  - Stella L
AUID- ORCID: 0000-0002-5489-7381
AD  - Department of Chemical Science and Technologies, University of Rome Tor Vergata, 
      00133, Rome, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200529
PL  - United States
TA  - J Chem Inf Model
JT  - Journal of chemical information and modeling
JID - 101230060
RN  - 0 (Phosphopeptides)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Humans
MH  - Molecular Dynamics Simulation
MH  - Phosphopeptides/metabolism
MH  - Protein Binding
MH  - *Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics
MH  - Signal Transduction
MH  - *src Homology Domains
PMC - PMC8007070
COIS- The authors declare no competing financial interest.
EDAT- 2020/05/13 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/03/29
CRDT- 2020/05/13 06:00
PHST- 2020/05/13 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/05/13 06:00 [entrez]
PHST- 2021/03/29 00:00 [pmc-release]
AID - 10.1021/acs.jcim.0c00307 [doi]
PST - ppublish
SO  - J Chem Inf Model. 2020 Jun 22;60(6):3157-3171. doi: 10.1021/acs.jcim.0c00307. 
      Epub 2020 May 29.