Philippe Youkharibache, Ph.D.

Philippe Youkharibache, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute


Dr. Youkharibache’s research aims at: 1) understanding self-association determinants of proteins, especially cell surface and membrane proteins, at several levels of the molecular organization to provide a structural basis for therapeutic protein engineering; 2) developing methods, software, and databases to support the design and engineering of immuno oncology and antiviral therapeutics; and 3) improving the design and engineering of novel immunotherapeutic molecules in clinical trials to treat cancers.

Dr. Youkharibache uses macromolecular structure analysis and computational tools to discover hidden relationships within and between protein domains; he is an expert in macromolecular symmetry analysis. He has inspired, designed and managed the development of numerous successful scientific software packages in both commercial and academic environments, including tools for molecular modeling, computer-aided drug design, structure, and dynamics analysis, next-gen sequencing data analysis, protein structure symmetry analysis, and structural bioinformatics. 

His most recent work has been focused on 1) chimeric antigen receptors architecture, and its impact on T-cell function and 2) receptor binding domains from human endogenous retrovirus and zoonotic viruses to provide working hypotheses for the molecular mechanisms underlying biological function of these complex systems.

Areas of Expertise

1) protein domain architecture, 2) structural bioinformatics, 3) computational biology, 4) data science, 5) immunotherapy, 6) drug discovery 


Selected Key Publications

The Small β-Barrel Domain: A Survey-Based Structural Analysis

Youkharibache P, Veretnik S, Li Q, Stanek KA, Mura C, Bourne PE.
Structure. 27(1): 6-26, 2019. [ Journal Article ]

Protodomains: Symmetry-Related Supersecondary Structures in Proteins and Self-Complementarity

Youkharibache P.
Methods Mol Biol. 1958: 187-219, 2019. [ Journal Article ]

Systematic detection of internal symmetry in proteins using CE-Symm

Myers-Turnbull D, Bliven SE, Rose PW, Aziz ZK, Youkharibache P, Bourne PE, Prlić A.
J Mol Biol. 426(11): 2255-68, 2014. [ Journal Article ]

Pseudo-Symmetric Assembly of Protodomains as a Common Denominator in the Evolution of Polytopic Helical Membrane Proteins

Youkharibache P, Tran A, Abrol R.
J Mol Evol. 88(4): 319-344, 2020. [ Journal Article ]

iCn3D, a web-based 3D viewer for sharing 1D/2D/3D representations of biomolecular structures

Wang J, Youkharibache P, Zhang D, Lanczycki CJ, Geer RC, Madej T, Phan L, Ward M, Lu S, Marchler GH, Wang Y, Bryant SH, Geer LY, Marchler-Bauer A.
Bioinformatics. 36(1): 131-135, 2020. [ Journal Article ]

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Staff Scientist (NLM)
Tom Madej, Ph.D.


Journal of Molecular Evolution Cover - Vol. 88, Issue 4, May 2020

Pseudo-Symmetric Assembly of Protodomains as a Common Denominator in the Evolution of Polytopic Helical Membrane Proteins

Published Date


The polytopic helical membrane proteome is dominated by proteins containing seven transmembrane helices (7TMHs). They cannot be grouped under a monolithic fold or superfold. However, a parallel structural analysis of folds around that magic number of seven in distinct protein superfamilies (SWEET, PnuC, TRIC,FocA, Aquaporin, GPCRs) reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction during their evolution. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral transmembrane helical protodomains, consisting of 3 (or 4) helices. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for their evolutionary paths. It highlights the conformational plasticity inherent to fold formation itself, the role of structural as well as functional constraints in shaping that fold, and the usefulness of protodomains as a tool to probe convergent vs divergent evolution. In the case of FocA vs. Aquaporin, this protodomain analysis sheds new light on their potential divergent evolution at the protodomain level followed by duplication and parallel evolution of the two folds. GPCR domains, whose function does not seem to require symmetry, nevertheless exhibit structural pseudo-symmetry. Their construction follows the same protodomain assembly as any other pseudo-symmetric protein suggesting their potential evolutionary origins. Interestingly, all the 6/7/8TMH pseudo-symmetric folds in this study also assemble as oligomeric forms in the membrane, emphasizing the role of symmetry in evolution, revealing self-assembly and co-evolution not only at the protodomain level but also at the domain level.


Pseudo-Symmetric Assembly of Protodomains as a Common Denominator in the Evolution of Polytopic Helical Membrane Proteins. Youkharibache P, Tran A, Abrol R. J Mol Evol. 2020 May;88(4):319-344. doi: 10.1007/s00239-020-09934-4. Epub 2020 Mar 18. PMID: 32189026; PMCID: PMC7162841.

Methods in Molecular Biology - Protein Supersecondary Structures:  Methods and Protocols

Protodomains: Symmetry-Related Supersecondary Structures in Proteins and Self-Complementarity

Published Date


We will consider in this chapter supersecondary structures (SSS) as a set of secondary structure elements (SSEs) found in protein domains. Some SSS arrangements/topologies have been consistently observed within known tertiary structural domains. We use them in the context of repeating supersecondary structures that self-assemble in a symmetric arrangement to form a domain. We call them protodomains (or protofolds). Protodomains are some of the most interesting and insightful SSSs. Within a given 3D protein domain/fold, recognizing such sets may give insights into a possible evolutionary process of duplication, fusion, and coevolution of these protodomains, pointing to possible original protogenes. On protein folding itself, pseudosymmetric domains may point to a "directed" assembly of pseudosymmetric protodomains, directed by the only fact that they are tethered together in a protein chain. On function, tertiary functional sites often occur at protodomain interfaces, as they often occur at domain-domain interfaces in quaternary arrangements. First, we will briefly review some lessons learned from a previously published census of pseudosymmetry in protein domains (Myers-Turnbull, D. et al., J Mol Biol. 426:2255-2268, 2014) to introduce protodomains/protofolds. We will observe that the most abundant and diversified folds, or superfolds, in the currently known protein structure universe are indeed pseudosymmetric. Then, we will learn by example and select a few domain representatives of important pseudosymmetric folds and chief among them the immunoglobulin (Ig) fold and go over a pseudosymmetry supersecondary structure (protodomain) analysis in tertiary and quaternary structures. We will point to currently available software tools to help in identifying pseudosymmetry, delineating protodomains, and see how the study of pseudosymmetry and the underlying supersecondary structures can enrich a structural analysis. This should potentially help in protein engineering, especially in the development of biologics and immunoengineering.


Protodomains: Symmetry-Related Supersecondary Structures in Proteins and Self-Complementarity. Youkharibache P. Methods Mol Biol. 2019;1958:187-219. doi:10.1007/978-1-4939-9161-7_10. PMID: 30945220.