Day :
Keynote Forum
Wladek Minor
University of Virginia, USA
Keynote: The impact of reproducibility on structure based drug discovery
Time : 10:00-10:45
Biography:
Wladek Minor is a Harrison Distinguished Professor of Molecular Physiology and Biological Physics at University of Virginia. He is an expert in structural biology and data
mining. He is an author of over 190 papers that attracted over 41,000 of citations. His relative citations ratio is above 600. He has trained over 90 scientists that currently
pursue career in academia, government and industry
Abstract:
The drug discovery process depends on the veracity of every decision point on the path from initial experiments to FDA
approval, and erroneous data collected along the path can waste valuable time and resources. Th e presentation will discuss the
sources of uncertainty that aff ect the drug discovery process, focusing on factors that impact structure based drug design the most.
Th e selection of structures used as the basis of computations or data mining will be discussed in detail. All aspects of procedures
essential for structural validation and best practices for data management of all experimental steps will be also discussed
Keynote Forum
Tzu-Ching Meng
Academia Sinica, Taiwan
Keynote: Structural basis for PTPN3-p38γ resting-state complex involved in colon cancer progression
Time : 10:45-11:30
Biography:
Wladek Minor is a Harrison Distinguished Professor of Molecular Physiology and Biological Physics at University of Virginia. He is an expert in structural biology and data mining. He is an author of over 190 papers that attracted over 41,000 of citations. His Relative Citations Ratio is above 600.He trained over 90 scientists that currently pursue career in academia, government and industry.
Abstract:
The Ras signaling cascade acts as a key driver in human colon cancer progression. Among the modules in this pathway, p38γ
(MAPK12) and its specifi c protein tyrosine phosphatase PTPN3 (PTPH1) are critical regulators responsible for Ras oncogenic
activity. However, the molecular basis for their interaction remains elusive. We showed both p38γ and PTPN3 being highly expressed
in late-stage of human colon cancer tissues. Comprehensive structural information on the PTPN3-p38γ interaction is essential
to understand their cooperative activities in Ras-dependent malignancies. Employing an advanced hybrid method integrating
x-ray crystallography, small-angle x-ray scattering (SAXS), chemical cross-linking/mass spectrometry (CX-MS) and hydrogendeuterium
exchange (HDX), we have obtained a unique architecture of the PTPN3-phosphorylated p38γ complex. Moreover, we
showed that PTPN3 binds to unphosphorylated p38γ with micromolar affi nity. Enzyme kinetics studies revealed that the presence
of the PDZ binding motif of p38γ promotes the phosphatase activity of PTPN3. Using small-angle x-ray scattering, we found that
PTPN3 adopts a predominantly compact shape in the absence of p38γ. Aft er complex formation with unphosphorylated p38γ,
we observed an extended conformation that was clearly diff erent from that of the active state complex. Th rough chemical crosslinking
coupled with mass spectrometry, we confi rmed that the PDZ domain binds to the N-lobe region of unphosphorylated
p38γ, thereby forming an end-to-end complex assembly. Overall, our results show that PTPN3 and unphosphorylated p38γ may
form a resting-state complex, suggesting its unexpected function to promote colon cancer progression. Our structural data suggest
the presence of the active-state complex (left ) and the resting-state complex (right) between PTPN3 and p38γ Th e interaction of
PDZ domain in PTPN3 and the ETPL motif in p38γ drives the complex formation. We show that the resting-state complex may
promote oncogenic signaling involved in colon cancer progression.